CN101538246A - Pyrimidine amide compounds as pgds inhibitors - Google Patents

Pyrimidine amide compounds as pgds inhibitors Download PDF

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CN101538246A
CN101538246A CN200910138053A CN200910138053A CN101538246A CN 101538246 A CN101538246 A CN 101538246A CN 200910138053 A CN200910138053 A CN 200910138053A CN 200910138053 A CN200910138053 A CN 200910138053A CN 101538246 A CN101538246 A CN 101538246A
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phenyl
pyrimidine
formic acid
acid amides
methyl
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CN101538246B (en
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S·C·奥尔德斯
J·Z·姜
卢锦琪
马良
牟岚
H·R·芒森
J·S·萨博尔
S·图赖拉特奈姆
C·L·范德森
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Auin Thurber holding Co.
Auin Thurber Limited by Share Ltd.
Aventis Saab LLC
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Aventis Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

This invention is directed to a compound of formula (I): wherein R<1>, R<2>, R<3> and L<1> are as defined herein, a pharmaceutical composition comprising the compound, and the use of the compound to treat allergic and/or inflammatory disorders, particularly disorders such as allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD).

Description

Pyrimidine amide compounds as the PGDS inhibitor
The application is dividing an application of Chinese patent application 200680036578.6, and the applying date of original application is on October 4th, 2006, and denomination of invention is " as the pyrimidine amide compounds of PGDS inhibitor ".
Invention field
The present invention relates to pyrimidine amide compounds, its preparation method, comprise the pharmaceutical composition of these compounds, and their pharmaceutical uses in the treatment of the morbid state that can regulate by the inhibition of Prostaglandin D synthase.
Background of invention
Allergic rhinitis is modal atopic disorder, estimates that its popularity degree accounts for 5% to 22% of human total population, it is characterized in that sneezing, has a running nose and symptom such as nasal obstruction.Think that now these symptoms are to be caused by the multiple medium that mastocyte and other inflammatory cell discharge.Present therapeutical agent such as antihistaminic agent can tackle symptoms such as sneezing and have a running nose effectively, but very little to the effect of having a stuffy nose, and nasal obstruction influences a kind of key symptoms of patients ' life quality just.
Studies show that allergic rhinitis, bronchial asthma, anaphylaxis conjunctivitis and atopic dermatitis patients are carried out local allergen to stimulate, cause that PGD2 (PGD2) level raises rapidly in nasal cavity and bronchial irrigating solution, tears and the skin chamber liquid.PGD2 has many proinflammatory effects, for example increases the vascular permeability of conjunctiva and skin, increases the infiltration to conjunctiva and tracheae of nasal airways resistance, airway constriction and oxyphie.PGD2 is arachidonic main cyclooxygenase product, is produced by mastocyte when being subjected to immunostimulation.[Lewis, RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts L J II, Prostaglandin D2generation afteractivation of rat and human mast cells with anti-IgE (with the generation of PGD2 behind anti-IgE medicine activation rat and the human mast cell), J.Immunol.129,1627-1631,1982].The activated mastocyte is the main source of PGD2, is to cause one of anaphylactoid key factor in such as the illness of asthma, allergic rhinitis, anaphylaxis conjunctivitis, allergic dermatitis and other diseases.[Brightling CE, Bradding P, Pavord ID, Wardlaw AJ, New Insightsinto the role of the mast cell in asthma (the effect new explanation of mastocyte in asthma), Clin.Exp.Allergy 33,550-556,2003].
When sulfhydryl compound exists, because the katalysis of Prostaglandin D synthase (PGDS), isomerization will take place and form PGD2 in a kind of common prostaglandin(PG) precursor PGH2.PGDS has two kinds of isomeric form: L-PGDS and H-PGDS.H-PGDS is a kind of cytosol enzyme, and it is distributed in the peripheral tissues, and is positioned at antigen presenting cell, mastocyte, megalokaryocyte and Th2 lymphocyte.The effect of this product P GD2 is to be mediated by the acceptor of G-albumen coupling-D prostaglandin(PG) (DP) and crTH2.Consult (1) Prostaglandin D Synthase:Structure and Function (Prostaglandin D synthase: structure and function), T.Urade and O.Hayaishi, Vitamin andHormones, 2000,58,89-120, (2) J.J.Murray, N.Engl.J.Med., 1986Sept.25; 315 (13): 800, and people such as (3) Urade, J.Immunology 168:443-449,2002.
We believe that the formation that suppresses PGD2 will be influential to the nasal obstruction symptom, thereby will produce result of treatment to allergic rhinitis.In addition, we believe that also the PGDS inhibitor will also have result of treatment to many other indications such as bronchial asthma.
The existing report of PGDS inhibitor.According to reports, compound H QL-79 is a kind of faint PGDS inhibitor, and anti-asthmatic action (Matsusshita waits the people, Jpn.J.Pharamcol.78:11,1998) is arranged in cavy and rat model.Compound tranilast (Tranilast) is described to a kind of PGDS inhibitor.[Inhibitory Effect of Tranilast on Prostaglandin D Synthesase (tranilast is to the restraining effect of Prostaglandin D synthase), K.Ikai, M.Jihara, k.Fujii and Y.Urade.Biochemical Pharmacology, 1989,28,2773-2676].
Summary of the invention
The present invention relates to the compound of formula (I):
Figure A20091013805300181
Wherein:
R 1Be aryl, heteroaryl or (C 5-C 6)-cycloalkyl, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy;
R 2Be hydrogen or (C 1-C 4)-alkyl;
R 3Be-P (=O)-(alkoxyl group) 2, or Y 1Y 2N-SO 2-,
Cycloalkyl, cycloalkenyl group, aryl, heteroaryl, heterocyclic radical, heterocycloalkenyl, or polynaphthene aryl, each group is optional to be replaced by following groups:
Acyl group, cyano group, nitro, halogen, hydroxyl, carboxyl, amidino groups, R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-C (=O)-O-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, Y 1Y 2N-(C 1-C 4)-alkylidene group-SO 2-(C 1-C 4)-alkylidene group-, or
Alkyl, alkenyl, alkynyl, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphinyl, or alkyl sulphonyl, each group is optional to be replaced by following groups:
Halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, amino, alkylamino, dialkyl amido, carboxyl, or alkoxy carbonyl, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by following groups: oxo base or alkyl, or
Aryl, heteroaryl, aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy; or heterocyclic radical, each group is optional to be replaced by following groups: alkyl, haloalkyl, halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, or Y 1Y 2N-SO 2-, and
Work as R 3When being cycloalkyl, cycloalkenyl group, heterocyclic radical, heterocycloalkenyl or polynaphthene aryl, it is optional to be replaced by the oxo base;
L 1Be a key, or the optional (C that is replaced by hydroxyl 1-C 6)-alkylidene group, or work as R 3When being optional substituted cycloalkyl, cycloalkenyl group, aryl, heteroaryl, heterocyclic radical, heterocycloalkenyl or polynaphthene aryl, should (C 1-C 6)-alkylidene group also can choose wantonly by-P (=O)-(alkoxyl group) 2Replace;
R 4, R 5And R 6Be hydrogen or alkyl independently of one another,
R 7Be the optional alkyl that is replaced by hydroxyl, halogen or alkoxyl group, or
Aryl, heteroaryl, arylalkyl or heteroarylalkyl, the aryl of aryl wherein, heteroaryl or arylalkyl or heteroarylalkyl or heteroaryl can be chosen wantonly by following groups and replace: alkyl, haloalkyl, hydroxyl, carboxyl, alkoxy carbonyl, amino, alkylamino, dialkyl amido, halogen, alkoxyl group or halogenated alkoxy; And
Y 1And Y 2Be independently of one another:
Hydrogen,
The optional alkyl that is replaced by following groups:
Hydroxyl, carboxyl, halogen, amino, alkylamino, dialkyl amido, cycloalkyl amino, aminocarboxyl, alkyl amino-carbonyl, dialkyl amino carbonyl, cycloalkyl amino carbonyl,
The optional alkoxyl group that is replaced by hydroxyl,
Cycloalkyl, heterocyclic radical, aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen or haloalkyl, or
Optional by the cycloalkyl of carboxyl substituted, or
Y 1And Y 2With the nitrogen-atoms that links to each other with them, formation can contain and is selected from other heteroatomic heterocyclic radical in oxygen, nitrogen or the sulphur, and wherein this heterocyclic radical is optional is replaced by alkyl or oxo base;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another aspect of the present invention is pharmaceutical composition, it comprises formula (I) compound of medicine effective quantity, or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt, mixes with pharmaceutically acceptable carrier.
Another aspect of the present invention relates to methods of treatment, need the patient of treatment to use formula (I) compound by giving, or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt, treatment supersensitivity and/or inflammatory disorder are especially such as the obstacle of allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD).
Detailed Description Of The Invention
The definition of term
Used as mentioned and through explanation of the present invention, following term should be understood that to have following implication, unless otherwise specified:
" acyl group " means H-CO-or (aliphatic group or cyclic group)-CO-.Specific acyl group comprises the low-grade alkane acidyl that contains low alkyl group.Exemplary acyl group comprises formyl radical, ethanoyl, propionyl, 2-methylpropionyl, butyryl radicals, palmitoyl, acryl, propioloyl, and cyclohexyl-carbonyl.
" alkenyl " means and contains carbon-carbon double bond and the 2 straight or branched aliphatic groups to about 15 carbon atoms.Specific alkenyl contains 2 to about 12 carbon atoms.More specific alkenyl contains 2 to about 4 carbon atoms." side chain " means one or several low alkyl groups such as methyl, ethyl or propyl group link to each other with the thiazolinyl of a straight chain." low-grade alkenyl " means this chain and contains 2 to 4 carbon atoms of having an appointment, and can be straight or branched.Exemplary alkenyl comprises vinyl, propenyl, n-butene base, isobutenyl, 3-methyl but-2-ene base, positive pentenyl, heptenyl, octenyl, cyclohexyl butenyl, and the decene base.
" alkoxyl group " means alkyl-O-.Exemplary alkoxyl group comprise methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and heptan the oxygen base.
" alkoxy carbonyl " means alkyl-O-CO-.Exemplary alkoxy carbonyl comprises methoxycarbonyl, ethoxy carbonyl and tert-butoxycarbonyl.
" alkyl " means and contains the 1 straight or branched aliphatic hydrocarbon to about 20 carbon atoms.Specific alkyl contains 1 to about 12 carbon atoms.More specific is low alkyl group." side chain " means one or several low alkyl groups such as methyl, ethyl or propyl group link to each other with the alkyl of a straight chain." low alkyl group " means this straight chained alkyl and contains 1 to about 4 carbon atoms, can be straight or branched.
" alkylamino " means alkyl-NH-.Specific alkylamino is (C 1-C 6)-alkylamino.Exemplary alkylamino comprises methylamino and ethylamino.
" alkylidene group " means and contains the 1 divalence hydrocarbon to the straight or branched of about 15 carbon atoms.Specific alkylidene group is to contain 1 low-grade alkylidene to about 6 carbon atoms.Exemplary alkylidene group comprises methylene radical, ethylidene, propylidene and butylidene.
" alkyl sulphonyl " means alkyl-SO 2-.Specific alkyl sulphonyl is (C 1-C 6)-alkyl sulphonyl.Exemplary alkyl sulphonyl comprises CH 3-SO 2-and CH 3CH 2-SO 2-.
" alkylthio " means alkyl-S-.Exemplary alkylthio comprises CH 3-S-.
What " alkynyl " meant straight or branched contains a carbon carbon triple bond and 2 aliphatic hydrocarbons to about 15 carbon atoms.Specific alkynyl contains 2 to about 12 carbon atoms.More specific alkynyl contains 2 to about 6 carbon atoms." side chain " means one or several low alkyl groups such as methyl, ethyl or propyl group link to each other with the alkynyl of a straight chain." low-grade alkynyl " means this straight alkynyl and contains 2 to about 4 carbon atoms, can be straight or branched.Exemplary alkynyl comprises ethynyl, proyl, positive butynyl, 2-butyne base, 3-methyl butynyl, positive pentynyl, heptyne base, octyne base, and decynyl.
" aroyl " means aryl-CO-.Exemplary aroyl comprises benzoyl, and 1-naphthoyl and 2-naphthoyl.
" aryl " means aromatic monocyclic or the polycyclic system that contains 6 to 14 carbon atoms of having an appointment.Specific aryl contains 6 to 10 carbon atoms of having an appointment.Exemplary aryl comprises phenyl and naphthyl.
" alkoxy aryl " means arylalkyl-O-.Exemplary alkoxy aryl comprises benzyloxy and 1-naphthalene methoxyl group or 2-naphthalene methoxyl group.
" aryl-alkoxy carbonyl " means arylalkyl-O-CO-.Exemplary aryl-alkoxy carbonyl comprises phenyloxycarbonyl and naphthyloxy carbonyl.
" arylalkyl " mean arylalkyl-.Specific arylalkyl contains (C 1-C 6)-moieties.Exemplary arylalkyl comprises benzyl, 2-styroyl and menaphthyl.
" aryl alkylsulfonyl " means aryl-alkyl-SO 2-.Specific aryl alkylsulfonyl contains (C 1-C 6)-moieties.Exemplary aryl alkylsulfonyl comprises the benzyl alkylsulfonyl.
" aryl rings thiazolinyl " means condensed aryl and cycloalkenyl group.Aryl in the specific aryl rings thiazolinyl is that phenyl and this cycloalkenyl group are made up of about 5 to 7 annular atomses.Aryl rings thiazolinyl system has the ability to carry out any atom of bonded and combination by this cycloalkenyl group on partly.Exemplary aryl rings thiazolinyl comprises 1,2-dihydro naphthylidene and indenyl.
" cycloalkyl aryl " means condensed aryl and cycloalkyl.Aryl in the specific cycloalkyl aryl is that phenyl and this cycloalkyl are made up of about 5 to 6 annular atomses.Cycloalkyl aryl system carries out any atom of bonded and combination by having the ability on this cycloalkyl moiety.Exemplary cycloalkyl aryl comprises 1,2,3,4-tetrahydrochysene naphthylidene.
" aryl-heterocyclic thiazolinyl " means condensed aryl and heterocycloalkenyl.Aryl in the specific aryl-heterocyclic thiazolinyl is that phenyl and this heterocycloalkenyl are made up of about 5 to 6 annular atomses.Aryl-heterocyclic thiazolinyl system carries out any atom of bonded and combination by having the ability on this heterocycloalkenyl.The prefix that names such as azepine, oxa-or sulfo-are referred to as the heterocycloalkenyl part of aryl-heterocyclic thiazolinyl shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of aryl-heterocyclic thiazolinyl can be a basic nitrogen atom.The nitrogen of the heterocycloalkenyl part of aryl-heterocyclic thiazolinyl or sulphur atom also can be chosen wantonly and be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary aryl-heterocyclic thiazolinyl comprises 3H-indolinyl, 1H-2-oxo-quinolyl, 2H-1-oxo isoquinolyl, 1,2-dihydroquinoline base, 3, and 4-dihydroquinoline base, 1,2-dihydro-isoquinoline base, and 3,4-dihydro-isoquinoline base.
" aryl-heterocyclic base " means condensed aryl and heterocyclic radical.Aryl among the specific heterocyclic Ji Fangji is that phenyl and this heterocyclic radical are made up of about 5 to 6 annular atomses.The aryl-heterocyclic base has the ability to carry out any atom of bonded and combination by this heterocyclic radical on partly.The prefix that names such as azepine, oxa-or sulfo-are referred to as the heterocyclic radical part of aryl-heterocyclic base shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of aryl-heterocyclic base can be a basic nitrogen atom.But the nitrogen or the sulphur atom of the heterocyclic radical of aryl-heterocyclic base part also are oxidized to the person corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary aryl-heterocyclic base comprises indolinyl, 1,2,3,4-tetrahydro isoquinolyl, 1,2,3,4-tetrahydric quinoline group, 1H-2,3-xylylenimine-2-base, 2,3-dihydrobenzo [f] isoindole-2-base, and 1,2,3,4-tetrahydro benzo [g]-isoquinoline 99.9-2-base.
" aryloxy " means aryl-O-.Exemplary aryloxy comprises phenoxy group and naphthyloxy.
" aryloxy carbonyl " means aryl-O-CO-.Exemplary aryloxy carbonyl comprises phenyloxycarbonyl and naphthyloxy carbonyl.
" compound of the present invention " and suitable statement thereof under the situation that context allows, mean and comprise aforesaid formula (I) compound, its hydrate, solvate and N-oxide compound, and pharmacologically acceptable salt.Similarly, when mentioning intermediate, no matter whether propose the patent right requirement, under the situation that context allows, all mean the salt, N-oxide compound and the solvate that comprise them with regard to itself.
" cycloalkenyl group " means non-aromatic monocyclic or the polycyclic system that contains 3 to 10 carbon atoms of having an appointment, and specific is to contain to have an appointment 5 to 10 carbon atoms and contain a carbon-carbon double bond at least.The specific ring of this class ring-type system contains 5 to 6 annular atomses of having an appointment; And the specific ring of this class still be known as " rudimentary ".Exemplary monocycle cycloalkenyl group comprises cyclopentenyl, cyclohexenyl and cycloheptenyl.Exemplary many cycloalkenyl groups are norbornenes.
" cycloalkenyl group aryl " means condensed aryl and cycloalkenyl group.Specific cycloalkenyl group aryl aryl wherein is that phenyl and this cycloalkenyl group are made up of about 5 to 6 annular atomses.Cycloalkenyl group aryl system carries out any atom of bonded and combination by having the ability on this aryl moiety.Exemplary cycloalkenyl group aryl comprises 1,2-dihydro naphthylidene and indenyl.
" cycloalkenyl group heteroaryl " means condensed heteroaryl and cycloalkenyl group.Specific cycloalkenyl group heteroaryl heteroaryl wherein is made up of about 5 to 6 annular atomses, and this cycloalkenyl group is made up of about 5 to 6 annular atomses.Cycloalkenyl group heteroaryl system carries out any atom of bonded and combination by having the ability on this heteroaryl.The prefix that names such as azepine, oxa-or sulfo-are referred to as the heteroaryl moieties of cycloalkenyl group heteroaryl shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of cycloalkenyl group heteroaryl can be a basic nitrogen atom.The nitrogen-atoms of the heteroaryl moieties of cycloalkenyl group heteroaryl also can be chosen wantonly and be oxidized to corresponding N-oxide compound.Exemplary cycloalkenyl group heteroaryl comprises 5,6-dihydroquinoline base, 5, and 6-dihydro-isoquinoline base, 5,6-dihydro-quinoxaline base, 5,6-dihydroquinazoline base, 4,5-dihydro-1H-benzimidazolyl-, and 4,5-Er hydrogen benzoxazolyl.
" cycloalkyl " means non-aromatic monocyclic or the many ring fillings ring-type system that contains 3 to 10 carbon atoms of having an appointment, and specifically contains 5 to 10 carbon atoms of having an appointment.Specific ring-type system contains about 5 to 7 annular atomses; And the specific ring-type system of this class still be known as " rudimentary ".Exemplary monocyclic cycloalkyl comprises cyclopentyl, cyclohexyl and suberyl.Exemplary polycyclic naphthene base comprises 1-naphthalane base, norborneol alkyl and diamantane-(1-or 2-) base.
" cycloalkyl aryl " means condensed aryl and cycloalkyl.Aryl in the specific cycloalkyl aryl is that phenyl and this cycloalkyl are made up of about 5 to 6 annular atomses.Cycloalkyl aryl system carries out any atom of bonded and combination by having the ability on this cycloalkyl moiety.Exemplary cycloalkyl aryl comprises 1,2,3,4-tetrahydrochysene-naphthylidene.
" cycloalkylidene " means the divalent cycloalkyl that contains 4 to 8 carbon atoms of having an appointment.Specific cycloalkylidene contains 5 to 7 annular atomses of having an appointment; And the specific ring-type system of this class still be known as " rudimentary ".Bonding point on the cycloalkylidene comprises 1,1-, 1, and 2-, 1,3-or 1,4-bonding pattern, and also the stereochemistry relation of working as between the where applicable bonding point is a cis or trans.Exemplary monocycle cycloalkylidene comprise (1,1-, 1,2-or 1,3-) cyclohexylidene and (1,1-or 1,2-) cyclopentylidene.
" cycloalkyl heteroaryl " means condensed heteroaryl and cycloalkyl.Heteroaryl in the specific cycloalkyl heteroaryl is made up of about 5 to 6 annular atomses, and this cycloalkyl is made up of about 5 to 6 annular atomses.Cycloalkyl heteroaryl system has the ability to carry out any atom of bonded and combination by this heteroaryl.The prefix that names such as azepine, oxa-or sulfo-are referred to as the heteroaryl moieties of condensed cycloalkyl heteroaryl shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of cycloalkyl heteroaryl can be a basic nitrogen atom.But the nitrogen-atoms of the heteroaryl moieties of cycloalkyl heteroaryl also is oxidized to the person corresponding N-oxide compound.Exemplary cycloalkyl heteroaryl comprises 5,6,7,8-tetrahydric quinoline group, 5,6,7,8-tetrahydro isoquinolyl, 5,6,7,8-tetrahydroquinoxaline base, 5,6,7,8-tetrahydro quinazoline base, 4,5,6,7-tetrahydrochysene-1H-benzimidazolyl-, and 4,5,6,7-Si hydrogen benzoxazolyl.
" cyclic group " means cycloalkyl, cycloalkenyl group, heterocyclic radical or heterocycloalkenyl.
" dialkyl amido " means (alkyl) 2-N-.Specific dialkyl amido is (C 1-C 6Alkyl) 2-N-.Exemplary dialkyl amido comprises dimethylamino, diethylamino and methylethyl amino.
" halogeno-group " or " halogen " means fluorine, chlorine, bromine or iodine.Specific halogeno-group or halogen are fluorine or chlorines.
" halogenated alkoxy " means the alkoxyl group that is replaced by one to three halogen group.The lower alkoxy that specific halogenated alkoxy is replaced by one to three halogen.The lower alkoxy that the most specific halogenated alkoxy is replaced by a halogen.
" haloalkyl " means the alkyl that is replaced by one to three halogen group.The low alkyl group that specific haloalkyl is replaced by one to three halogen.The low alkyl group that the most specific haloalkyl is replaced by a halogen.
" 4-hetaroylpyrazol " means heteroaryl-CO-.Exemplary 4-hetaroylpyrazol comprises thiophene acyl group, nicotinoyl, pyrroles-2-base carbonyl, and pyridine acyl.
" heteroaryl " means aromatic monocyclic or the polycyclic system that contains 5 to 14 carbon atoms of having an appointment, and wherein one or several annular atomses are not carbon but assorted element, for example nitrogen, oxygen or sulphur in the ring-type system.Specific is the aromatics ring-type system that contains 5 to 10 carbon atoms of having an appointment, and contains 1 to 3 heteroatoms.More specific is the ring-type system that contains 5 to 6 annular atomses of having an appointment.The prefix that names such as azepine, oxa-or sulfo-are referred to as heteroaryl moieties shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of heteroaryl can be a basic nitrogen atom, and can randomly be oxidized to corresponding N-oxide compound.When heteroaryl was replaced by hydroxyl, it also comprised the tautomer that it is corresponding.Exemplary heteroaryl comprises pyrazinyl, thienyl, isothiazolyl oxazolyl, pyrazolyl, furyl, pyrryl, 1,2, the 4-thiadiazolyl group, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1,2-a] pyridine, imidazo [2,1-b] thiazolyl, benzofuryl, azaindolyl, benzimidazolyl-, benzothienyl, the thienopyridine base, the Thienopyrimidine base, pyrrolopyridinyl, imidazopyridyl, the benzo-aza indyl, 1,2, the 4-triazinyl, benzothiazolyl, imidazolyl, indyl, indolizine base isoxazolyl, isoquinolyl, isothiazolyl oxadiazole base, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, 1,3, the 4-thiadiazolyl group, thiazolyl, thienyl, and triazolyl.
" heteroarylalkyl " mean heteroaryl-alkyl-.Specific heteroarylalkyl contains (C 1-C 4)-moieties.Exemplary heteroarylalkyl comprises tetrazolium-5-ylmethyl.
" heteroaryl ring thiazolinyl " means condensed heteroaryl and cycloalkenyl group.Specific heteroaryl ring thiazolinyl heteroaryl wherein is made up of about 5 to 6 annular atomses, and this cycloalkenyl group is made up of about 5 to 6 annular atomses.The heteroaryl ring thiazolinyl carries out any atom of bonded and combination by having the ability on this cycloalkenyl group.The prefix that names such as azepine, oxa-or sulfo-are referred to as the heteroaryl moieties of heteroaryl ring thiazolinyl shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of heteroaryl ring thiazolinyl can be a basic nitrogen atom.The nitrogen-atoms of the heteroaryl moieties of heteroaryl ring thiazolinyl also can randomly be oxidized to corresponding N-oxide compound.Exemplary heteroaryl ring thiazolinyl comprises 5,6-dihydroquinoline base, 5, and 6-dihydro-isoquinoline base, 5,6-dihydro-quinoxaline base, 5,6-dihydroquinazoline base, 4,5-dihydro-1H-benzimidazolyl-, and 4,5-Er hydrogen benzoxazolyl.
" heteroaryl ring alkyl " means condensed heteroaryl and cycloalkyl.Specific heteroaryl ring alkyl wherein heteroaryl is made up of about 5 to 6 annular atomses, and this cycloalkyl is made up of about 5 to 6 annular atomses.The heteroaryl ring alkyl carries out any atom of bonded and combination by having the ability on this cycloalkyl.The prefix that names such as azepine, oxa-or sulfo-are referred to as the heteroaryl moieties of condensed heteroaryl ring alkyl shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of heteroaryl ring alkyl can be a basic nitrogen atom.The nitrogen-atoms of the heteroaryl moieties of heteroaryl ring alkyl also can randomly be oxidized to corresponding N-oxide compound.Exemplary heteroaryl ring alkyl comprises 5,6,7,8-tetrahydric quinoline group, 5,6,7,8-tetrahydro isoquinolyl, 5,6,7,8-tetrahydroquinoxaline base, 5,6,7,8-tetrahydro quinazoline base, 4,5,6,7-tetrahydrochysene-1H-benzimidazolyl-, and 4,5,6,7-Si hydrogen benzoxazolyl.
" heteroaryl heterocycloalkenyl " means condensed heteroaryl and heterocycloalkenyl.Specific heteroaryl heterocycloalkenyl wherein heteroaryl is made up of about 5 to 6 annular atomses, and heterocycloalkenyl is made up of about 5 to 6 annular atomses.Heteroaryl heterocycloalkenyl system carries out any atom of bonded and combination by having the ability on this heterocycloalkenyl.Names such as azepine, oxa-or sulfo-are referred to as the heteroaryl of heteroaryl heterocycloalkenyl or the prefix of heterocycloalkenyl part shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of heteroaryl nitrogen heterocyclic thiazolinyl can be a basic nitrogen atom.The nitrogen of the heteroaryl moieties of heteroaryl heterocycloalkenyl or sulphur atom also can randomly be oxidized to corresponding N-oxide compound.The nitrogen or the sulphur atom of the heteroaryl of heteroaryl heterocyclic radical or heterocyclic radical part also can randomly be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary heteroaryl heterocycloalkenyl comprises 7,8-dihydro [1,7] naphthyridinyl, 1,2-dihydro [2,7]-naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl, 1,2-dihydro-1,7-naphthyridinyl, 1,2-dihydro-1,8-naphthyridinyl, and 1,2-dihydro-2,6-naphthyridinyl.
" heteroaryl heterocyclic radical " means condensed heteroaryl and heterocyclic radical.Specific heteroaryl heterocyclic radical wherein heteroaryl is made up of about 5 to 6 annular atomses, and heterocyclic radical is made up of about 5 to 6 annular atomses.The heteroaryl heterocyclic radical carries out any atom of bonded and combination by having the ability on this heterocyclic radical.Names such as azepine, oxa-or sulfo-are referred to as the heteroaryl of condensed heteroaryl heterocyclic radical or the prefix of heterocyclic radical part shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of condensed heteroaryl heterocyclic radical can be a basic nitrogen atom.The nitrogen of the heteroaryl moieties of heteroaryl heterocyclic radical or sulphur atom also can randomly be oxidized to corresponding N-oxide compound.The nitrogen or the sulphur atom of the heteroaryl of heteroaryl heterocyclic radical or heterocyclic radical part also can randomly be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary heteroaryl heterocyclic radical comprises 2,3-dihydro-1H-pyrroles [3,4-b] quinoline-2-base, 1,2,3,4-tetrahydro benzo [b] [1,7] naphthyridines-2-base, 1,2,3,4-tetrahydro benzo [b] [1,6] naphthyridines-2-base, 1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-base, 1,2,3,4-tetrahydrochysene-9H-pyrido [4,3-b] indoles-2-base, 2,3-dihydro-1H-pyrrolo-[3,4-b] indoles-2-base, 1H-2,3,4,5-tetrahydrochysene azepine
Figure A20091013805300271
And [3,4-b] indoles-2-base, 1H-2,3,4,5-tetrahydrochysene azepine
Figure A20091013805300272
And [4,3-b] indol-3-yl, 1H-2,3,4,5-tetrahydrochysene azepine And [4,5-b] indoles-2-base, 5,6,7,8-tetrahydrochysene [1,7] naphthyridinyl, 1,2,3,4-tetrahydrochysene [2,7] naphthyridinyl, 2, [1,4] dioxin is [2,3-b] pyridyl also for the 3-dihydro, 2,3-dihydro-[1,4] dioxin also [2,3-b] pyridyl, 3,4-dihydro-2H-1-oxa-[4,6] phthalazinyl, 4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridyl, 6,7-dihydro [5,8] phthalazinyl, 1,2,3,4-tetrahydrochysene [1,5]-naphthyridinyl, 1,2,3,4-tetrahydrochysene [1,6] naphthyridinyl, 1,2,3,4-tetrahydrochysene [1,7] naphthyridinyl, 1,2,3,4-tetrahydrochysene [1,8] naphthyridinyl, and 1,2,3,4-tetrahydrochysene [2,6] naphthyridinyl.
" heteroaryl oxygen base " means heteroaryl-O-.Exemplary heteroaryloxy comprises pyridyl oxygen base.
" heterocycloalkenyl " means non-aromatic monocyclic or the polynuclear hydrocarbon ring-type system that contains 3 to 10 carbon atoms of having an appointment, wherein one of this ring-type system or several annular atomses are not carbon but assorted element, for example nitrogen, oxygen or sulphur atom, and contain a carbon-carbon double bond or carbon-to-nitrogen double bon at least.Specific non-aromatics ring bodies is to contain have an appointment 5 to 10 carbon atoms and 1 to 3 heteroatoms.More specific is the ring-type system that contains 5 to 6 annular atomses of having an appointment; And the specific ring of this class still be known as " rudimentary ".The prefix that names such as azepine, oxa-or sulfo-are referred to as the heterocycloalkenyl part shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of heterocycloalkenyl can be a basic nitrogen atom.The nitrogen of heterocycloalkenyl or sulphur atom also can randomly be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary monocycle nitrogen heterocyclic thiazolinyl comprises 1,2,3,4-tetrahydrochysene hydrogenated pyridine base, 1,2-dihydropyridine base, 1,4-dihydropyridine base, 1,2,3,6-tetrahydro pyridyl, 1,4,5,6-tetrahydro-pyrimidine base, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl and 2-pyrazolinyl.Exemplary oxa-cycloalkenyl group comprises 3,4-dihydro-2H-pyranyl, dihydrofuran base, and fluoridize the dihydrofuran base.Exemplary many epoxies heterocycloalkenyl is 7-oxabicyclo [2.2.1] heptenyl.Exemplary monocycle sulfo-heterocycloalkenyl comprises dihydrobenzene sulfenyl and dihydrogen phosphorothioate pyranyl.
" heterocycloalkenyl aryl " means condensed aryl and heterocycloalkenyl.Specific heterocyclic alkenyl aryl aryl wherein is that phenyl and this heterocycloalkenyl are made up of about 5 to 6 annular atomses.The heterocycloalkenyl aryl carries out any atom of bonded and combination by having the ability on this aryl.The prefix that names such as azepine, oxa-or sulfo-are referred to as the heterocycloalkenyl part of condensed heterocycle alkenyl aryl shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of heterocycloalkenyl aryl can be a basic nitrogen atom.The nitrogen or the sulphur atom of the heterocycloalkenyl part of heterocycloalkenyl aryl also can randomly be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary heterocycloalkenyl aryl comprises 3H-indolinyl, IH-2-oxo-quinolyl, 2H-1-oxo isoquinolyl, 1,2-dihydroquinoline base, 3, and 4-dihydroquinoline base, 1,2-dihydro-isoquinoline base, and 3,4-dihydro-isoquinoline base.
" heterocycloalkenyl heteroaryl " means condensed heteroaryl and heterocycloalkenyl.Specific heterocyclic thiazolinyl heteroaryl wherein heteroaryl is made up of about 5 to 6 annular atomses, and this heterocycloalkenyl is made up of about 5 to 6 annular atomses.The heterocycloalkenyl heteroaryl is to carry out any atom of bonded and bonded by having the ability on this heteroaryl.Names such as azepine, oxa-or sulfo-are referred to as the heteroaryl of heterocycloalkenyl heteroaryl or the prefix of heterocycloalkenyl part shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of nitrogen heterocyclic thiazolinyl heteroaryl can be a basic nitrogen atom.The nitrogen of the heteroaryl moieties of heterocycloalkenyl heteroaryl or sulphur atom also can randomly be oxidized to corresponding N-oxide compound.The nitrogen or the sulphur atom of the heteroaryl of heterocycloalkenyl heteroaryl or heterocyclic radical part also can randomly be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary heterocycloalkenyl heteroaryl comprises 7,8-dihydro [1,7] naphthyridinyl, 1,2-dihydro [2,7]-naphthyridinyl, 6,7-dihydro-3H-imidazo [4,5-c] pyridyl, 1,2-dihydro-1,5-naphthyridinyl, 1,2-dihydro-1,6-naphthyridinyl, 1,2-dihydro-1, the 7-naphthyridinyl, 1,2-dihydro-1,8-naphthyridinyl and 1,2-dihydro-2,6-naphthyridinyl.
" heterocyclic radical " means and contains have an appointment 3 to 10 carbon atom non-aromatics saturated mono rings or polycyclic system, and wherein one of the ring-type system or several atoms are not carbon but assorted element, for example nitrogen, oxygen or sulphur.Specific is that this ring-type system contains about 5 to 10 carbon atoms and 1 to 3 heteroatoms.The specific ring of this class ring-type system contains 5 to 6 annular atomses of having an appointment; And the specific ring of this class still be known as " rudimentary ".The prefix that names such as azepine, oxa-or sulfo-are referred to as the heterocyclic radical part shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of heterocyclic radical can be a basic nitrogen atom.The nitrogen of heterocyclic radical or sulphur atom also can randomly be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary monocyclic heterocycles base comprises piperidyl, pyrrolidyl, piperazinyl, morpholinyl, thio-morpholinyl, thiazolidyl, 1,3-dioxolanyl, 1,4-alkyl dioxin, tetrahydrofuran base, tetrahydrochysene thiophenyl, and tetrahydrochysene sulfo-pyranyl.
" heterocyclic radical aryl " means condensed aryl and heterocyclic radical.Specific heterocyclic Ji Fangji aryl wherein is that phenyl and this heterocyclic radical are made up of about 5 to 6 annular atomses.The heterocyclic radical aryl is to carry out any atom of bonded and bonded by having the ability on this aryl moiety.The prefix that names such as azepine, oxa-or sulfo-are referred to as the heterocyclic radical part of heterocyclic radical aryl shows to have at least nitrogen, oxygen or a sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of heterocyclic radical aryl can be a basic nitrogen atom.The nitrogen or the sulphur atom of the heterocyclic radical part of heterocyclic radical aryl also can randomly be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary heterocyclic radical aryl comprises indolinyl, 1,2,3,4-tetrahydro isoquinolyl, 1,2,3,4-tetrahydric quinoline group, 1H-2,3-xylylenimine-2-base, 2,3-dihydrobenzo [f] isoindole-2-base, and 1,2,3,4-tetrahydro benzo [g]-isoquinoline 99.9-2-base.
" heterocyclic radical heteroaryl " means condensed heteroaryl and heterocyclic radical.Specific heterocyclic base heteroaryl wherein heteroaryl is made up of about 5 to 6 annular atomses, and this heterocyclic radical is made up of about 5 to 6 annular atomses.The heterocyclic radical heteroaryl is to carry out any atom of bonded and bonded by having the ability on this heterocyclic radical.Names such as azepine, oxa-or sulfo-are referred to as the heteroaryl of heterocyclic radical heteroaryl or the prefix of heterocyclic radical part shows to have at least nitrogen, oxygen or sulphur atom to exist as annular atoms respectively.The nitrogen-atoms of heterocyclic radical heteroaryl can be a basic nitrogen atom.The nitrogen of the heteroaryl moieties of heterocyclic radical heteroaryl or sulphur atom also can randomly be oxidized to corresponding N-oxide compound.The nitrogen of the heteroaryl of heterocyclic radical heteroaryl or heterocyclic radical part or sulphur atom also can be chosen wantonly by ground and be oxidized to corresponding N-oxide compound, S-oxide compound or S, S-dioxide.Exemplary heterocyclic radical heteroaryl comprises 2,3-dihydro-1H-pyrroles [3,4-b] quinoline-2-base, 1,2,3,4-tetrahydro benzo [b] [1,7] naphthyridines-2-base, 1,2,3,4-tetrahydro benzo [b] [1,6] naphthyridines-2-base, 1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles-2-base, 1,2,3,4-tetrahydrochysene-9H-pyrido [4,3-b] indoles-2-base, 2,3-dihydro-1H-pyrrolo-[3,4-b] indoles-2-base, 1H-2,3,4,5-tetrahydrochysene azepine
Figure A20091013805300291
[3,4-b] indoles-2-base, 1H-2,3,4,5-tetrahydrochysene azepine
Figure A20091013805300292
[4,3-b] indol-3-yl, 1H-2,3,4,5-tetrahydrochysene azepine
Figure A20091013805300293
[4,5-b] indoles-2-base, 5,6,7,8-tetrahydrochysene [1,7] naphthyridinyl, 1,2,3,4-tetrahydrochysene [2,7] naphthyridinyl, 2, [1,4] dioxin is [2,3-b] pyridyl also for the 3-dihydro, 2,3-dihydro-[1,4] dioxin also [2,3-b] pyridyl, 3,4-dihydro-2H-1-oxa-[4,6] phthalazinyl, 4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridyl, 6,7-dihydro [5,8] phthalazinyl, 1,2,3,4-tetrahydrochysene [1,5]-naphthyridinyl, 1,2,3,4-tetrahydrochysene [1,6] naphthyridinyl, 1,2,3,4-tetrahydrochysene [1,7] naphthyridinyl, 1,2,3,4-tetrahydrochysene [1,8] naphthyridinyl, and 1,2,3,4-tetrahydrochysene [2,6] naphthyridinyl.
" polynaphthene aryl " means a kind of polycyclic system, it contains and at least one non-at least one aromatic ring of aromatic ring condensed, can be saturated, also can be undersaturated, and this ring-type system also can contain one or several heteroatomss, for example nitrogen, oxygen or sulphur.Exemplary polynaphthene aryl comprises aryl rings thiazolinyl, cycloalkyl aryl, aryl-heterocyclic thiazolinyl, aryl-heterocyclic base, cycloalkenyl group aryl, cycloalkyl aryl, cycloalkenyl group heteroaryl, cycloalkyl heteroaryl, heteroaryl ring thiazolinyl, heteroaryl ring alkyl, heteroaryl heterocycloalkenyl, heteroaryl heterocyclic radical, heterocycloalkenyl aryl, heterocycloalkenyl heteroaryl, heterocyclic radical aryl, and the heterocyclic radical heteroaryl.Specific polynaphthene aryl is to contain a dicyclo with a non-aromatic ring condensed aromatic ring, and this polynaphthene aryl also can contain one or several heteroatomss, for example nitrogen, oxygen or sulphur.
" patient " comprises human and other Mammals.
" pharmacologically acceptable salt " refers to the nontoxic inorganic and organic acid addition salt of The compounds of this invention, and base addition salt.This class salt can this compound final separate and purifying during prepare at the scene, or by allowing the pure compound of free alkali form and suitable organic acid or mineral acid react respectively, isolate formed salt then and prepared.In some cases, these compounds itself can make basic site on the molecule take place protonated and form a kind of amphoteric inner salt.
Exemplary acid salt comprises hydrobromate; hydrochloride; vitriol; hydrosulfate; phosphoric acid salt; nitrate; acetate; oxalate; valerate; oleate; palmitate; stearate; lauroleate; borate; benzoate; lactic acid salt; phosphoric acid salt; tosylate; Citrate trianion; maleate; fumarate; succinate; tartrate; naphthoate; mesylate; glucoheptose salt; Lactobionate; sulfamate; malonate; salicylate; propionic salt; methylene radical-bis-beta-hydroxyethyl base naphthoate; gentisate; isethionate; two toluoyl base tartrates; mesylate; esilate; benzene sulfonate; tosilate; cyclohexyl-n-sulfonate and lauryl sulfonate.Consult S.M.Berge, wait the people, " Pharmaceutical Salts " (medicinal salts), J. Pharm.Sci., 66, 1-19 (1977) quotes as a reference herein.The preparation of base addition salt can realize by allowing the pure compound of free acid form react, separate then formed salt respectively with suitable organic bases or mineral alkali.Base addition salt comprises pharmaceutically acceptable metal-salt and amine salt.Proper metal salt comprises sodium, potassium, calcium, barium, zinc, magnesium and aluminium salt.A kind of specific base addition salt is sodium salt or sylvite.Suitable mineral alkali additive salt is that the alkali of this metal comprises sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide etc. from the preparation of the alkali of metal.The base addition salt of suitable amine makes from some amine, and these amine have enough alkalescence forming stable salt, and comprises those amine that often use in the medical chemistry especially, because they have hypotoxicity and the acceptability that is suitable for medical usage.Ammonia, quadrol, N-methylglucosamine, Methionin, arginine, ornithine, choline, N, amino acid such as the Methionin and the arginine of N '-dibenzyl-ethylenediamin, chloroprocaine, diethanolamine, PROCAINE HCL, PHARMA GRADE, N-benzyl styroyl amine, diethylamine, piperazine, three (hydroxymethyl)-aminomethane, Tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, Trimethylamine 99, ethamine, alkalescence, and dicyclohexylamine.
The physical property that " solvate " means The compounds of this invention and one or several solvent molecules is associated.This physical property is associated and is comprised hydrogen bonding.In some cases, for example when the lattice of crystalline solid contained one or several solvent molecules, solvate can be separated." solvate " comprises solution phase and insoluble solvent thing.Specific solvate comprises hydrate, ethylate and methylate.
Special embodiment of the present invention
Special embodiment of the present invention is formula (I) compound, wherein R 1Be phenyl, five yuan or six membered heteroaryl, or (C 5-C 6)-cycloalkyl, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 1Be phenyl or five yuan or six membered heteroaryl, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another specific embodiment of the present invention is formula (I) compound, wherein R 1Be phenyl or five yuan or six membered heteroaryl, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy, or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt, condition is to work as R 1When being phenyl or six membered heteroaryl, it only at the ortho position or a position be optionally substituted.
Another special embodiment of the present invention is formula (I) compound, wherein R 1Be phenyl, pyridyl, thiazolyl, imidazolyl or oxo di azoly, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 1Be phenyl or pyridyl, each group can be chosen wantonly in the ortho position or a position is replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 1Be to choose the phenyl that is replaced by following groups wantonly: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 1Be can be in the ortho position or the optional phenyl that is replaced by following groups in a position: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 1Be to choose the phenyl that is replaced by halogen wantonly; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 1Be can be in the ortho position or the optional phenyl that is replaced by halogen in a position; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 1Be 2-fluorophenyl or 3-fluorophenyl; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 2Be hydrogen; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 2It is methyl; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein L 1It is a key; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein L 1Be (C 1-C 3)-alkylidene group; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein L 1Be-CH 2-; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein:
R 3Be cycloalkyl, cycloalkenyl group, aryl, heteroaryl, heterocyclic radical, heterocycloalkenyl, or the polynaphthene aryl,
Each group all can be chosen wantonly by following groups and replace:
Acyl group, cyano group, nitro, halogen, hydroxyl, carboxyl, amidino groups, R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-C (=O)-O-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, Y 1Y 2N-(C 1-C 4)-alkylidene group-SO 2-(C 1-C 4)-alkylidene group-, or
Alkyl, alkenyl, alkynyl, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphinyl, or alkyl sulphonyl, each group is optional to be replaced by following groups:
Halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, amino, alkylamino, dialkyl amido, carboxyl, or alkoxy carbonyl, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by following groups: oxo base or alkyl, or
Aryl, heteroaryl, aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryl oxygen base; or heterocyclic radical, each group is optional to be replaced by following groups: alkyl, haloalkyl, halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, or Y 1Y 2N-SO 2-, and
Work as R 3When being cycloalkyl, cycloalkenyl group, heterocyclic radical, heterocycloalkenyl or polynaphthene aryl, it is also optional to be replaced by the oxo base;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 3Be phenyl, pyridyl, thiazolyl, imidazolyl, oxo di azoly, imidazolyl, pyrimidyl, thiophenyl, oxazolyl, cycloalkyl, benzoxazolyl, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, THP trtrahydropyranyl, piperidyl, furyl, benzo [1,3] dioxolyl, benzothiazolyl, imidazolidyl, indazolyl, benzimidazolyl-, indyl, benzofuryl, or 1,3-dihydro-benzo [c] isothiazolyl, each group is optional to be replaced by following groups:
Acyl group, cyano group, nitro, halogen, hydroxyl, carboxyl, amidino groups,
R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-C (=O)-O-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, Y 1Y 2N-(C 1-C 4)-alkylidene group-SO 2-(C 1-C 4)-alkylidene group-, or
Alkyl, alkenyl, alkynyl, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphinyl, or alkyl sulphonyl, each group is optional to be replaced by following groups:
Halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, amino, alkylamino, dialkyl amido, carboxyl, or alkoxy carbonyl, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by following groups: oxo base or alkyl, or
Aryl, heteroaryl, aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryl oxygen base; or heterocyclic radical, each group is optional to be replaced by following groups: alkyl, haloalkyl, halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, or Y 1Y 2N-SO 2-, and
Work as R 3Be cycloalkyl, THP trtrahydropyranyl, piperidyl, imidazolidyl, or 1, during 3-dihydro-benzo [c] isothiazolyl, it is also chosen wantonly and is replaced by the oxo base;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein:
R 3Be phenyl, pyridyl, thiazolyl, imidazolyl, oxo di azoly, imidazolyl, pyrimidyl, thiophenyl, oxazolyl, cycloalkyl, benzoxazolyl, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, THP trtrahydropyranyl, piperidyl, furyl, benzo [1,3] dioxolyl, benzothiazolyl, imidazolidyl, indazolyl, benzimidazolyl-, indyl, benzofuryl, or 1,3-dihydro-benzo [c] isothiazolyl, each group is optional to be replaced by following groups:
Nitro, halogen, hydroxyl, carboxyl, amidino groups, R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphonyl, aryl, heteroaryl, or alkyl, it is optional to be replaced by following groups:
Halogen, carboxyl, alkoxy carbonyl, aryl or heteroaryl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by the oxo base, or
Heterocyclic radical, it is optional by Y 1Y 2N-replaces, and
Work as R 3Be cycloalkyl, THP trtrahydropyranyl, piperidyl, imidazolidyl, or 1, during 3-dihydro-benzo [c] isothiazolyl, it is also chosen wantonly and is replaced by the oxo base; And
Y 1And Y 2Be hydrogen, cycloalkyl independently of one another, or the optional alkyl that is replaced by following groups: hydroxyl, alkoxyl group, amino, alkylamino, dialkyl amido, heteroaryl, or the optional heterocyclic radical that is replaced by alkyl;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 3Be the optional phenyl that is replaced by following groups:
Acyl group, cyano group, nitro, halogen, hydroxyl, carboxyl, amidino groups,
R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-C (=O)-O-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, Y 1Y 2N-(C 1-C 4)-alkylidene group-SO 2-(C 1-C 4)-alkylidene group-, or
Alkyl, alkenyl, alkynyl, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphinyl, or alkyl sulphonyl, each group is optional to be replaced by following groups:
Halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, amino, alkylamino, dialkyl amido, carboxyl, or alkoxy carbonyl, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by following groups: oxo base or alkyl, or
Aryl, heteroaryl, aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryl oxygen base; or heterocyclic radical, each group is optional to be replaced by following groups: alkyl, haloalkyl, halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, or Y 1Y 2N-SO 2-,
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein:
R 3Be the optional phenyl that is replaced by following groups:
Nitro, halogen, hydroxyl, carboxyl, amidino groups, R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphonyl, aryl, heteroaryl, or
The optional alkyl that is replaced by following groups:
Halogen, carboxyl, alkoxy carbonyl, aryl or heteroaryl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by the oxo base, or
Optional by Y 1Y 2The heterocyclic radical that N-replaces, and
Y 1And Y 2Be hydrogen, cycloalkyl independently of one another, or the optional alkyl that is replaced by following groups: hydroxyl, alkoxyl group, amino, alkylamino, dialkyl amido, heteroaryl, or the optional heterocyclic radical that is replaced by alkyl,
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein R 3Be the optional phenyl that is replaced by following groups:
Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, alkyl sulphonyl, or
By Y 1Y 2N-SO 2-, R 7-SO 2-NR 6The alkyl of-replacement;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Another special embodiment of the present invention is formula (I) compound, wherein:
R 3Be the optional phenyl that is replaced by following groups:
Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, alkyl sulphonyl, or
By Y 1Y 2N-SO 2-, R 7-SO 2-NR 6The alkyl of-replacement; And
Y 1And Y 2Be hydrogen, cycloalkyl independently of one another, or the optional alkyl that is replaced by following groups: hydroxyl, alkoxyl group, amino, alkylamino, dialkyl amido, heteroaryl, or the optional heterocyclic radical that is replaced by alkyl,
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
The compound that another special embodiment of the present invention is formula (I), they are:
2-phenyl-pyrimidine-5-formic acid benzyl acid amides,
2-pyridin-4-yl-pyrimidine-5-formic acid phenyl amide,
2-pyridin-3-yl-pyrimidine-5-formic acid phenyl amide,
2-pyridine-2-base-pyrimidine-5-formic acid phenyl amide,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide,
2-(4-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide,
2-(2-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide,
2-phenyl-pyrimidine-5-formic acid (2,2-dioxo-2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid [1-(1H-imidazoles-2-ylmethyl-piperidin-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (6-dimethylamino-pyridin-3-yl methyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(2-tetramethyleneimine-1-base-ethyl)-benzoxazoles-6-yl]-acid amides,
2-phenyl-pyrimidine-5-formic acid 4-sulfamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(4-sulfamyl-phenyl)-ethyl]-acid amides,
(R)-2-phenyl-pyrimidine-5-formic acid [4-(2-Yang Dai oxazolidine-4-ylmethyl)-phenyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid (6-acetylaminohydroxyphenylarsonic acid pyridin-3-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (3-formamyl-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (3-methylamino formyl radical-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (4-hydroxyl-cyclohexyl)-acid amides,
4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-ethyl formate,
2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-ethyl acetate,
4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-formic acid,
2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-acetate,
2-phenyl-pyrimidine-5-formic acid 4-methyl sulfamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 4-dimethylamino alkylsulfonyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid (3,5-two fluoro-phenyl)-acid amides,
2-phenyl-pyrimidine-5-pyridine carboxylic acid-2-base acid amides,
2-phenyl-pyrimidine-5-formic acid thiazol-2-yl acid amides,
2-phenyl-pyrimidine-5-formic acid (3-sulfamyl-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (2-oxo-1,2-dihydro-pyrimidine-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (4-sulfamyl-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid pyrimidine-4-base acid amides,
2-phenyl-pyrimidine-5-formic acid (1-pyridin-3-yl methyl-piperidin-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(2-oxo-imidazolidine-1-yl)-ethyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(1H-imidazol-4 yl)-ethyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-ylmethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (3-trifluoromethyl-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (2H-pyrazole-3-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (1-methyl-piperidin-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid pyrimidine-2-base acid amides,
2-(3,5-two fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
2-(2,5-two fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
2-(4-difluorophenyl)-4-methylpyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides,
2-(2-pyridyl)-pyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides,
2-(3-pyridyl)-4-methyl-pyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-ethyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-oxyethyl group-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-cyclopropyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-hydroxyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-methoxyl group-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-methoxyl group-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(4-methoxyl group-butyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-cyclohexyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxyl-1,1-dimethyl-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-morpholine-4-base-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-piperidines-1-base ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(1-methyl-tetramethyleneimine-2-yl)-ethyl sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(1-ethyl-tetramethyleneimine-2-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(1H-imidazol-4 yl)-ethyl sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine 5-formic acid 3-[3-(2-methyl-piperidines-1-yl)-propyl group sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-tetramethyleneimine-1-base propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-dimethylamino-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-diethylamino-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-dimethylamino-2,2-dimethyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(5-dimethylamino-amyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-diisopropylaminoethyl-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-(methanesulfonamido-methyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-[(propane-2-sulfuryl amino)-methyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-methyl sulfamyl methyl-benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-(sec.-propyl sulfamyl-methyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(methylsulfonyl amino-methyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(propane-2-sulfuryl amino)-methyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl methyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(sec.-propyl sulfamyl-methyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (2-methylsulfonyl amino-pyridine-4-ylmethyl)-acid amides,
2-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides,
2-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrimidine-5-formic acid 4-sulfamyl-benzamide,
2-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(morpholine-4-alkylsulfonyl)-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 3,4-dimethoxy-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid (2-benzo [1,3] dioxole-5-base ethyl)-acid amides,
2-phenyl-pyrimidine 5-formic acid (1H-indazole-5-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid 4-[1,2,3] thiadiazoles-5-yl)-the benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
4-methyl-2-pyridine-2-base-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 4-morpholine-4-base benzyl acid amides,
6-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1H-benzimidazolyl-2 radicals-methyl-formiate,
6-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1H-benzimidazolyl-2 radicals-formic acid,
2-phenyl-pyrimidine-5-formic acid (cumarone-5-ylmethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid 4-methylsulfonyl amino-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 4-formamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 3-(2-hydroxyl-ethyl sulfamyl)-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 4-(morpholine-4-alkylsulfonyl)-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(2-amino-4-methyl-thiazole-5-yl)-ethyl]-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
4-{[(2-phenyl-pyrimidine-5-carbonyl)-amino]-benzyl }-diethyl phosphonate,
4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-butyl)-diethyl phosphonate,
4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-ethyl)-diethyl phosphonate,
Phenyl-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-methyl)-diethyl phosphonate,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methylsulfonyl)-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (1-methylsulfonyl-piperidines-3-ylmethyl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (1-dimethylamino alkylsulfonyl-piperidines-3-ylmethyl)-acid amides,
2-(phenyl)-pyrimidine-5-formic acid 3-methylsulfonyl amino-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-ethanoyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-oxo-piperazine-1-alkylsulfonyl)-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid (2-sulfamyl-ethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (2-dimethylamino alkylsulfonyl-ethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amides,
4-methyl-2-phenyl-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amides
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl) acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides,
2-cyclohexyl-pyrimidine-5-formic acid phenyl amide,
2-phenyl-pyrimidine-5-formic acid 3-amino-benzyl acid amides,
2-(3-pyridyl)-pyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides,
2-pyrazol-1-yl-pyrimidine-5-formic acid 4-sulfamyl-benzyl acid amides,
2-(2-methyl-thiazole-4-yl)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (thiophene-2-ylmethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (4-methyl-oxazoles-2-yl)-acid amides,
Methoxyimino-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-ethyl acetate,
2-phenyl-pyrimidine-5-formic acid (5-methyl sulfane base-[1,3,4] thiadiazoles-2-yl)-acid amides,
2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-benzothiazole-5-ethyl formate,
(R)-2-phenyl-pyrimidine-5-formic acid (1-phenyl-ethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid [3-(1H-tetrazolium-5-yl)-phenyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid (1-first miaow base-piperidin-4-yl methyl)-acid amides,
5-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1H-indole-3-carboxylic acid acid amides,
2-phenyl-pyrimidine-5-formic acid [3-(2-amino-thiazolyl--4-yl)-phenyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid 4-[2-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-ethyl]-thiazol-2-yl }-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid [2-(tetramethyleneimine-1-alkylsulfonyl)-ethyl]-acid amides,
[3-({ [2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino }-methyl)-benzyl]-t-butyl carbamate,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(pyridine-2-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-hydroxyl-2,2-dimethyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxy-2-methyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(tetrahydrochysene-pyrans-4-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(4-hydroxyl-butyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(2-hydroxyl-oxyethyl group)-ethyl sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(tetrahydrofuran (THF)-2-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-isobutyl-sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (5-sec.-propyl sulfamyl-pyridin-3-yl methyl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (5-methyl sulfamyl-pyridin-3-yl methyl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (2-methyl sulfamyl-pyridin-4-yl methyl)-acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid (2-methyl sulfamyl-pyridin-4-yl methyl)-acid amides, or
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid (5-sec.-propyl sulfamyl-pyridin-3-yl methyl)-acid amides, or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
Also comprise pharmaceutical composition within the scope of the present invention, it comprises the The compounds of this invention of medicine effective quantity, mixes with pharmaceutically acceptable carrier.
The compounds of this invention is the PGDS inhibitor, therefore can be used for treating the obstacle of supersensitivity and/or inflammatory disorder, especially allergic rhinitis, asthma and/or chronic obstructive pulmonary disease (COPD) and so on.
Correspondingly, another aspect of the present invention is related to the method for the patient treatment of suffering from allergic rhinitis and/or asthma, comprises formula (I) compound to patient's drug administration significant quantity.
The treatment of mentioning herein should be understood to include prophylactic treatment that suppresses PGDS and the treatment of having made a definite diagnosis acute or the chronic or physiological disorder relevant with PGDS, suffers from this sick patient or alleviates relative physiological situation and cure basically.Physiological disorder discussed herein comprises some but is not all possible clinical setting of having reason to take resisting allergic rhinitis and/or treating asthma.Exper ienced personnel understand the various situations that need treatment very much in this area.
In fact, The compounds of this invention can pharmaceutically acceptable formulation, be applied to people and other animal by locality or general method of application, comprise in oral, suction, rectum, nasal cavity, oral cavity, hypogloeeis, vagina, colon, injection (comprising in subcutaneous, intramuscular, vein, intracutaneous, the sheath and epidural), the brain pond, and intraperitoneal is used.Should be appreciated that specific approach can change with the person's that is subjected to the medicine physical appearance.
" pharmaceutically acceptable formulation " refers to the formulation of The compounds of this invention, comprise, for example tablet, drageeing, pulvis, elixir, syrup, the liquid preparation that comprises suspension, sprays, suction tablet, lozenge, emulsion, solution, particle, capsule and suppository, and be used for injection liquid preparations, comprise Liposomal formulation.Its technology and prescription can find in Lei Shi pharmacy complete works (Remington ' sPharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition) usually.
A special aspect of the present invention provides the The compounds of this invention of using with pharmaceutical compositions.
Depend on method of application and formulation, pharmaceutically acceptable carrier comprises at least a component that is selected from following pharmaceutically acceptable carrier: thinner, dressing, assistant agent, vehicle or media, and as sanitas, weighting agent, disintegrating agent, wetting agent, emulsifying agent, emulsion stabilizing agent, suspension agent, isotonic agent, sweeting agent, seasonings, perfume compound, tinting material, antiseptic-germicide, anti-mycotic agent, other therapeutical agent, lubricant, absorption delays or promotor and dispersion agent.
Exemplary suspension agent comprises ethoxylation isooctadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitol acid anhydride ester, Microcrystalline Cellulose, inclined to one side aluminium hydroxide, wilkinite, agar and tragacanth gum, or the mixture of these materials.
Exemplary antiseptic-germicide with prophylaxis of microbial effect and anti-mycotic agent comprise p-Hydroxybenzoate, butylene-chlorohydrin, phenol, Sorbic Acid etc.
Exemplary isotonic agent comprises sugar, sodium-chlor etc.
The exemplary absorption delayer that is used for delayed absorption comprises aluminum monostearate and gelatin.
The exemplary absorption enhancer that is used to increase absorption comprises dimethyl sulfoxide (DMSO) and related analogs.
Exemplary thinner, solvent, media, solubilizing agent, emulsifying agent and emulsion stabilizing agent comprise water, chloroform, sucrose, ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, tetrahydrofurfuryl alcohol, peruscabin, polyvalent alcohol, propylene glycol, 1,3 butylene glycol, glycerine, polyoxyethylene glycol, dimethyl formamide,
Figure A20091013805300441
60,
Figure A20091013805300442
60, hexadecanol/stearyl alcohol mixture, tetradecyl alcohol, glyceryl monostearate and bay sodium alkyl sulfate, sorbitan fatty(acid)ester, vegetables oil (as Oleum Gossypii semen, peanut oil, sweet oil, Viscotrol C and sesame oil) and injectable organic ester such as ethyl oleate etc., or the suitable mixture of these materials.
Exemplary vehicle comprises lactose, Trisodium Citrate, lime carbonate and Lin Suanergai.
Exemplary disintegrating agent comprises the silicates of starch, alginic acid and some complexing.
Exemplary lubricant comprises Magnesium Stearate, Sodium Lauryl Sulphate BP/USP, talcum powder, and high molecular weight polyethylene glycol.
The regulation that must observe in the chemical property (as solubility) of active compound, the concrete mode of using and the medication process is depended in the selection of pharmaceutically acceptable carrier usually.
Be suitable for Orally administered pharmaceutical composition of the present invention and can be made into independently unit such as solid dosage, as every dose of capsule, cachet or tablet that contains the predetermined dose activeconstituents, or powder or particle; Also can be made into the water base or non-water base suspension of liquid dosage form such as solution, perhaps oil-in-water emulsion or water in oil emulsion.Activeconstituents also can be made into bolus, electuary or paste.
The formulation that " solid dosage " means The compounds of this invention is a solid-state form, for example capsule, tablet, pill, powder, drageeing or particle.In this solid dosage, The compounds of this invention mixes with at least a inert excipient commonly used (or carrier), as Trisodium Citrate or Lin Suanergai or (a) weighting agent or extender, starch for example, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid, (b) tackiness agent, carboxymethyl cellulose for example, the alginic acid salt, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic, (c) wetting Agent for Printing Inks, glycerine for example, (d) disintegrating agent, agar for example, lime carbonate, potato or tapioca (flour), alginic acid, the silicates of some complexing and yellow soda ash, (e) solution retarding agent, paraffin for example, (f) absorption enhancer, quaternary ammonium compound for example, (g) wetting agent, for example hexadecanol and glyceryl monostearate, (h) sorbent material, for example kaolin and wilkinite, (i) lubricant, for example talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP, (j) opalizer, (k) buffer reagent, and the promoting agent that can discharge The compounds of this invention in the slowly-releasing mode in an enteron aisle part.
Tablet can be suppressed or molded mode prepares, and choosing wantonly has one or more ancillary components.Compressed tablets can by with activeconstituents with free-flowing form such as powder or particle, randomly with tackiness agent, lubricant, inert diluent, sanitas, tensio-active agent or dispersant, in suitable machine, suppress forming again.Vehicle such as lactose, Trisodium Citrate, lime carbonate, Lin Suanergai, disintegrating agent such as starch, alginic acid and some can be used with the complicated silicates that lubricants such as Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum powder combine.With the wetting powdered compounds mixture of inert liquid diluent, can in suitable machine, be molded as molded tablet.Tablet is dressing or indentation randomly, also can make contained activeconstituents be able to slow or controlled release by preparation.
Solids composition also can be used as the weighting agent of soft capsule and hard capsule, is vehicle with lactose and high molecular weight polyethylene glycol etc.
If desired, and for more effective distribution, compound can or be attached to a kind of slowly-releasing or target application system with the microcapsule sealing, biological example compatible, biodegradable polymer matrix is (as d, l-rac-Lactide-glycolide copolymer), liposome and microsphere, and carry out subcutaneous injection or intramuscularly by a kind of technology that is called as subcutaneous or intramuscular, make this compound in two weeks or longer time, be able to slowly-releasing constantly.This compound can be sterilized in every way, for example, filters with sterilizing filter, or degerming agent is added the sterile solid pharmaceutical composition, is dissolved in sterilized water or other aseptic injection medium before use again.
" liquid dosage form " means the active compound of using to the patient is to be in liquid form, for example pharmaceutically acceptable emulsion, solution, suspension, syrup and elixir.Except that active compound, liquid dosage form can contain inert diluent commonly used in this area, for example solvent, solubilizing agent and emulsifying agent etc.
When using water base suspension, the reagent that they can contain emulsifying agent or promote to suspend.
The pharmaceutical composition that is suitable for topical application means the preparation that exists to be suitable for the local form of using of patient.Can be with well-known local ointment, ointment, pulvis, sprays and inhalation, gelifying agent (water base or alcohol radical), the emulsifiable paste that uses in this preparation preparation cost field; Perhaps, add a kind of matrix, make that compound can be via the controlled release of skin barrier with the patch form application.When being mixed with ointment, activeconstituents can use with paraffin or water-soluble ointment base.Perhaps, activeconstituents can be mixed with emulsifiable paste by the oil-in-water emulsifiable paste matrix.Be suitable for comprising eye drops that wherein activeconstituents system dissolves or is suspended in a kind of appropriate carriers, especially the aqueous solvent of this activeconstituents at the preparation of eye topical application.Be suitable for comprising the lozenge that contains activeconstituents in the flavoured base that this matrix is sucrose and gum arabic or tragacanth gum normally at the preparation that oral cavity partial is used; Also comprise the pastille that contains activeconstituents in the inert base, this inert base for example is gelatin and glycerine, or sucrose and gum arabic; Also be included in the mouth wash shua that contains activeconstituents in the suitable liquid vehicle.
The oil phase of emulsion pharmaceutical composition can be grouped into by known one-tenth in known manner.Though this can only be made up of emulsifying agent mutually, it preferably contain by at least a emulsifying agent and a kind of fat or oil or with the fatty and oily mixture that both are formed.In special embodiment, hydrophilic emulsifying agent uses with the lipophilic emulsifier as stablizer.This emulsifying agent constitutes emulsifying wax separately or with stablizer, then constitutes the emulsification ointment base with oil ﹠ fat, and the latter forms the oiliness disperse phase of cream formulation.
If desired, the water of emulsifiable paste matrix for example can comprise the polyvalent alcohol of 30%w/w at least, the alcohol that promptly contains two or more hydroxyls, as propylene glycol, butane 1,3-glycol, N.F,USP MANNITOL, Sorbitol Powder, glycerine and polyoxyethylene glycol (comprising PEG 400) and composition thereof.Preferably, the preparation of topical application should contain the compound that promotes to absorb or promote activeconstituents transdermal or other affected area.
Can be used for the oils of composition or the selection of fat be based on and obtains required character.Therefore, emulsifiable paste preferably should be the product of non-grease, not painted and easy flush away, and has suitable denseness and leak out from flexible pipe or other container avoiding.The alkyl ester of straight or branched, monobasic or binary all can use as two isopropyl myristates, decyl oleate, Wickenol 111, butyl stearate, palmitinic acid-2-ethylhexyl or the branched ester mixture that is called as Crodamol CAP.Depend on required character, can use or be used in combination these auxiliary agents separately.Perhaps, also can use high-melting-point lipid such as white soft wax and/or whiteruss or other mineral oil.
The pharmaceutical composition that is suitable for rectum or vaginal application means the preparation that exists with the form that is suitable for the use of patient's per rectum or vagina, and contains at least a The compounds of this invention.Suppository is a kind of special form of this preparation, The compounds of this invention and suitable nonirritant excipient or carrier such as theobroma oil, polyoxyethylene glycol or certain suppository can be prepared with wax blended mode.These carriers are solid at normal temperatures but are liquid when body temperature, therefore can melt and discharge active ingredient in rectum or vaginal canal.
Can be with the pharmaceutical composition that injection system is used via muscle, intravenously, intraperitoneal and/or subcutaneous the injection.Pharmaceutical composition of the present invention can be formulated in the liquor, especially in the damping fluid of physical compatibility such as Han Keshi (Hank) solution or woods Ge Shi (Ringer) solution.In addition, said composition can be mixed with solid-state form and dissolving or suspension again again before using.In freeze dried form is also included within.This preparation is aseptic, and comprise emulsion, suspension, moisture and anhydrous injection solution, can contain suspension agent and thickening material and oxidation inhibitor, damping fluid, fungistat, and said preparation and the expection person's that is subjected to the medicine blood etc. is oozed, and be adjusted to the solute of proper pH value.
Be suitable for the pharmaceutical composition of the present invention that via intranasal application or inhalation route are used, mean the composition that exists with the form that is suitable for the use of patient's via intranasal application or inhalation route.This composition can contain powder carrier, its particle diameter for 1 to 500 micron scope for example (comprise the scope between 20 and 500 microns, with 5 microns be increment, for example 30 microns, 35 microns etc.).Its carrier is the suitable pharmaceutical composition of liquid, for example as nasal cavity spray or drops and the pharmaceutical composition of using, comprises the aqueous solution or the oil solution of activeconstituents.The composition that is suitable for using in the aerosol mode can prepare according to the conventional method, and can send with other therapeutical agent.The induction type therapeutical agent is easy to use by metered dose inhaler or any suitable Diskus, as Eclipse,
Figure A20091013805300481
Or
Figure A20091013805300482
Described in the 5th, 176, No. 132 patents of the WO2004/026380 application for patent and the U.S..
The actual dose level of the contained activeconstituents of the present composition can change, so that determine the significant quantity of activeconstituents, makes the patient produce required therapeutic response to certain specific pharmaceutical composition and application process.Therefore, the dosage level of selecting for any particular patient depends on various factorss such as desirable therapeutic action, depend on route of administration, the cause of disease and the seriousness that depend on desirable treatment time length, disease, patient's the state of an illness, body weight, sex, diet and age, the type of every kind of activeconstituents and tire, absorption, metabolism and/or excretory speed and other factor.
The TDD of the The compounds of this invention that patient's single every day or gradation are used can be, for example, every day by per kilogram of body weight about 0.001 to 100mg/kg, particularly 0.01 to 10mg/kg/ day.For example, grownup every day, to 100mg/kg, particularly about 0.01 to 10mg/kg by the inhalation dose normally about 0.01 of per kilogram of body weight; Be about 0.01 to 100mg/kg by the oral dosage of per kilogram of body weight every day, and particularly about 0.1 to 70mg/kg; More especially 0.5 to 10mg/kg; Be about 0.01 to 50mg/kg by the intravenously application dosage of per kilogram of body weight every day, and particularly 0.01 to 10mg/kg.The per-cent of active ingredient can change in the composition, but it must constitute certain ratio, to obtain a certain suitable dosage.The content of units dosage composition can be the part of dosage every day, forms dosage every day by some unitary doses.Obviously, the unitary dose of several forms can almost be used simultaneously.In order to obtain the ideal therapeutic action, can use a certain dosage continually as required and as far as possible.Some patient may promptly react to higher or lower dosage, may find that also much lower dosage has been enough to keep.For other patients,, have necessity and carry out 1 to 4 dose long-term treatment every day according to each concrete patient's physiological requirement.Self-evident, for other patients, be necessary to take every day and be no more than potion or two doses.
Said preparation can be prepared into unit dosage form with well-known any method in the pharmaceutics field.These methods comprise the step that pharmacy activity component is combined with the carrier that constitutes one or more ancillary components.Usually, these preparations with liquid vehicle or the solid carrier of pulverizing very carefully or the two all even combination nearly, then, if be necessary, make product shaping with active ingredient.
These preparations can place in unitary dose or the multi-dose container, and for example the phial of Mi Feng ampoule and band plug and can be preserved under lyophilisation condition, only need to add before using sterile liquid carrier such as water for injection.Instant injection solution and the suspension of preparing can be from aforesaid that class sterilized powder, particle and tablet preparation.
The compounds of this invention can be by using or adopting known method to prepare.So-called known method is meant the method for narrating in exhausted method before this or the document, and for example R.C.Larock is in those methods described in the Comprehensive Organic Transformations (VCH publishers, 1989).
In the described hereinafter reaction, wishing that final product has under the situation of some reactive functional groups, have these functional groups of necessary protection, for example hydroxyl, amino, imino-, sulfenyl or carboxyl are not wished the reaction that takes place to avoid their participation.Can use traditional protecting group according to the way of standard, for example, can consult this literary composition: T.W.Greene and P.G.M.Wuts, Protecting Groupsin Organic Synthesis (blocking group in the organic synthesis), the 3rd edition, John Wiley﹠amp; Sons, Inc., 1999.
Formula (I) and R wherein 2Be the compound of hydrogen, can be by the method shown in following scheme I preparation, promptly allow wherein R 1Amidine compound as herein defined, with the reagent react of formula (A), forming the compound of formula (B), the latter is directly or via the hydrolysate of its formula (C) and formula (D) and L wherein 1And R 3Amine generation coupling as herein defined.
Scheme I
Figure A20091013805300491
Formula (I) and R wherein 2Be (C 1-C 4The compound of)-alkyl can be by the method shown in following scheme II preparation, promptly allows a kind of wherein R 1Amidine compound as herein defined, with the reagent react of formula (E), forming the compound of formula (F), the latter is the hydrolysate of (G) and formula (D) and L wherein directly or via its structural formula 1And R 3Amine generation coupling as herein defined.
Scheme II
The compounds of this invention also can prepare by the change of other compound of the present invention.
Should be appreciated that The compounds of this invention may contain some asymmetric center.These asymmetric centers can be respectively R configuration or S configuration.It will be apparent to one skilled in the art that some compound of the present invention also can show geometric isomerism.Should be appreciated that, the present invention includes the various geometrical isomers of above-mentioned formula (I) compound and steric isomer and composition thereof, comprise racemic mixture.Such isomer can be separated from their mixture by using or adopting known method such as chromatographic technique and recrystallization technology, perhaps also can prepare respectively from the suitable isomer of its intermediate.
The compounds of this invention, their preparation method and their biologic activity will become clearer by checking following examples, provide these embodiment to illustrate for example, should not be understood that it is to limit the scope of the invention.The compounds of this invention is to differentiate by analytical procedure as described below.
Mass spectrum (MS) is to write down with Micromass LCT mass spectrograph.Described method is positive electro-spray ionization, and scanning mass-to-charge ratio m/z is 100 to 1000.
300MHz 1The H NMR (Nuclear Magnetic Resonance) spectrum ( 1H NMR) be to write down down in normal temperature with Varian Mercury (300MHz) the type spectrograph of being furnished with ASW 5mm probe. 1Chemical shift among the H NMR (δ) be object of reference as interior target tetramethylsilane (TMS) with hundred very much son one (ppm) be unit representation.
In following embodiment and preparation, and the rest part of the application's book, used term will have following connotation: " kg " refers to kilogram, " g " refers to gram, and " mg " refers to milligram, and " μ g " refers to microgram, " mol " refers to mole, and " mmol " refers to mmole, and " M " refers to mol, " mM " refer to mmole/liter, " μ M " refer to micromoles per liter, " nM " refer to nmole/liter, " L " refers to rise, " mL " or " ml " refers to milliliter, " μ L " refers to microlitre, " ℃ " refer to centigradetemperature, " mp " or " m.p. " refers to fusing point, " bp " or " b.p. " refers to boiling point, " mmHg " refers to the pressure in mmhg, and " cm " refers to centimetre, and " nm " refers to nanometer, " abs. " refers to absolute, " conc. " refers to spissated, and " c " refers to the concentration in grams per milliliter, and " rt " refers to room temperature, " TLC " refers to thin-layer chromatography, " HPLC " refers to high performance liquid chromatography, and " i.p. " refers to Intraabdominal, and " i.v. " refers to intravenous, " s "=unimodal, " d "=bimodal; " t "=triplet; " q "=quartet; " m "=multiplet, " dd "=doublet of doublet; " br "=broad peak, " LC "=liquid chromatography, " MS "=mass spectroscopy, " ESI/MS "=electrospray ionization/mass spectroscopy, " R T"=retention time; " M "=molion; " PSI "=pound/square inch; " DMSO "=dimethyl sulfoxide (DMSO), " DMF "=N, dinethylformamide; " DCM "=methylene dichloride; " HCl "=hydrochloric acid, the approaching assay method of " SPA "=flicker, " EtOAc "=ethyl acetate, " PBS "=phosphate buffered saline buffer, " IUPAC "=International Union of Pure and Applied Chemistry, " MHz "=megahertz, " MeOH "=methyl alcohol, " N "=equivalent, " THF "=tetrahydrofuran (THF), " min "=minute, " N 2"=nitrogen, " MeCN " or " CH 3CN "=acetonitrile, " Et 2O "=ether, " TFA "=trifluoroacetic acid, "～"=approximately, " rt "=room temperature, " MgSO 4"=sal epsom, " Na 2SO 4"=sodium sulfate, " NaHCO 3"=sodium bicarbonate, " Na 2CO 3"=yellow soda ash; " MCPBA "=3-chloro peroxide acid; " NMP "=N-Methyl pyrrolidone; " PS-DCC "=polymer supported dicyclohexylcarbodiimide; " LiOH "=lithium hydroxide; " PS-triamine "=polymer supported triamine, " PGH2 "=PGH2, " PGD2 "=PGD2; " PGE2 "=prostaglandin E2, " hPGDS "=hematopoiesis PGD2 synthase, " GSH "=gsh (reduced form), " EIA "=enzyme immunoassay, " KH 2PO 4"=potassium primary phosphate, " K 2HPO 4"=potassium hydrogen phosphate, " FeCl 2"=iron protochloride, " MOX "=methoxyl group amine; " EtOH "=ethanol, " DMSO "=dimethyl sulfoxide (DMSO).
Embodiment
Embodiment 1:
2-phenyl-pyrimidine-5-formic acid benzyl acid amides
Figure A20091013805300521
Step 1: use N 2Cleaning is furnished with the 250mL three neck round-bottomed flasks of magnetic stirring apparatus and reflux exchanger.In flask, successively add 3 then, 3-dimethoxy methyl propionate (5.22g, 35.3mmol), anhydrous 1,2-glycol dimethyl ether (25mL), anhydrous formic acid methyl esters (5mL), 60% sodium hydride (1.7g, 42.5mmol), with this mixture heating up to 40-50 ℃ until stopping the hydrogen of overflowing.This reaction mixture is cooled off in an ice-water bath, and stir to spend the night and let alone to reach lentamente room temperature.Add anhydrous diethyl ether (25mL), and at N 2In filter the suspension generated, with anhydrous diethyl ether (10mL) washing, and vacuum-drying 2 hours, promptly The sodium salt of 2-dimethoxy-methyl-3-hydroxyl-methyl acrylate(3.51g, 50%) is for Powdered. 1H NMR(CD 3OD)：δ3.33(s，6H)，3.60(s，3H)，5.31(s，1H)，8.89(s，1H)。(consult P.Zhichkin, D.J.Fairfax, S.A.Eisenbeis, Synthesis, 2002,720-722.)
Step 2: in dry DMF (4mL) solution of benzamidine hydrochloride hydrate (2mmol), add 2- The sodium salt of dimethoxy-methyl-acrolactic acid methyl esters(0.46g, 2.32mmol), and at N 2Under existing this reaction mixture was heated 1 hour in 100 ℃.Reaction is cooled to room temperature and adds entry (15mL).After adding entry, promptly can be observed the product precipitation.By solid collected by filtration, water (2.5mL) washing and vacuum-drying, promptly 2-phenyl-pyrimidine-5-methyl-formiate(0.32g, 74%).(consult P.Zhichkin, D.J.Fairfax, S.A.Eisenbeis, Synthesis, 2002,720-722.)
Step 3: (volume ratio is 1: 1: 1,120mL) will to be dissolved in MeOH, THF and water mixture 2-phenyl-pyrimidine-5-methyl-formiate(3.15g) and the solution of LiOH (0.71g) under room temperature, stir and spend the night.MeOH and THF are evaporated to generate an aqueous solution.With this aqueous solution of 5% hcl acidifying with between pH regulator to 2.5 and 3.Filter out precipitation and wash with water, dry in a vacuum, promptly get 2.94g (～100%) 2-phenyl-pyrimidine-5-formic acid, be solid product.MS：201(M+H)。
Step 4: will 2-phenyl-pyrimidine-5-formic acid(80mg), I-hydroxybenzotriazole (92mg) and polymer supported carbodiimide (640mg, 1.25mmol/g) the jolting 30min and add benzylamine (43mg) under room temperature of the mixture in 8mL DCM.In jolting under the room temperature after 1.5 days, add the PS-triamine (295mg, 4.08mmol/g).With this mixture jolting constantly at room temperature 16 hours.Filter out solid and wash with DCM.Filtrate is concentrated, promptly 2-phenyl-pyrimidine-5-formic acid benzyl acid amides(98mg, 85%) is solid product.MS:290 (M+H); 1H NMR (CDCl 3): 9.17 (s, 2H), 8.50 (d, 2H), 7.52-7.55 (m, 3H), 7.36-7.40 (m, 5H), 6.54 (wide, H), 4.69-4.71 (d, 2H); IC 50=10nM.
Embodiment 2
2-pyridin-4-yl-pyrimidine-5-formic acid phenyl amide
(1g, (1.46g 7.36mmol), heats 1h with reaction mixture in 100 ℃ to the sodium salt of dry DMF 6.35mmol) (12mL) solution adding 2-dimethoxy-methyl-acrolactic acid methyl esters to step 1. in nitrogen atmosphere to different nicotinoyl amidine hydrochloride.Reaction is cooled to room temperature and adds entry (48mL).By filtering collecting precipitation, wash with water and vacuum-drying, promptly 2-pyridin-4-yl-pyrimidine-5-formic acid Methyl esters(1.2g, 88%).MS：216(M+H)； 1H NMR(300MHz，CD 3OD)：δ4.00(s，3H)，8.44(d，2H)，8.73(d，2H)，9.38(s，2H)。
(1.11g, 5.18mmol) (1M 5.18mL) is dissolved in MeOH (7.25mL) to step 2., stirs under room temperature and spends the night with the LiOH aqueous solution with 2-pyridin-4-yl-pyrimidine-5-methyl-formiate.Remove MeOH in a vacuum, and handle this aqueous solution with 3N HCl the pH value is adjusted between 2 and 3.Filter out solid product, wash with water and dry in a vacuum, promptly 2-pyridin-4-yl-pyrimidine-5-formic acid(1g, 96%) is solid product.MS：202(M+H)。
Step 3. is with 2-pyridin-4-yl-pyrimidine-5-formic acid (100mg, 0.5mmol), I-hydroxybenzotriazole (76.1mg, 0.56mmol) and PS-DCC (539mg, 1.25mmol/g, 0.66mmol) mixture jolting 15min under room temperature in DMF (8mL), and adding aniline (31mg, 0.33mmol).In jolting under the room temperature after 18 hours, add the PS-triamine (398mg, 3.75mmol/g, 1.49mmol), and with this mixture jolting constantly at room temperature 18 hours.Filter out solid and wash with DCM.Filtrate is concentrated, promptly 2-pyridin-4-yl-pyrimidine-5-formic acid phenyl amide(15mg, 16%) is solid product.MS：277(M+H)。
Embodiment 3
2-pyridin-3-yl-pyrimidine-5-formic acid phenyl amide
Figure A20091013805300541
Step 1. to nicotinoyl amidine hydrochloride (1g, dry DMF 6.35mmol) (12mL) solution add 2-dimethoxy-methyl-3-hydroxyl-methyl acrylate sodium salt (1.46g, 7.36mmol), at N 2In the atmosphere reaction mixture was heated 3 hours in 100 ℃.Then, reaction is cooled to room temperature and add entry (48mL).By filtering collecting precipitation, wash with water and vacuum-drying, promptly 2-pyridin-3-yl-pyrimidine-5- Methyl-formiate(0.7g, 51%).MS：216(M+H)。
(0.73g 3.32mmol) is dissolved in MeOH (5mL) with the 1M LiOH aqueous solution (3.32mL) to step 2., stirs under room temperature and spends the night with 2-pyridin-3-yl-pyrimidine-5-methyl-formiate.Remove MeOH in a vacuum, handle this aqueous solution with 3N HCl the pH value is adjusted to～2-3.Filter out solid product, wash with water and dry in a vacuum, promptly 2-pyridin-3-yl-pyrimidine-5-formic acid(0.2g, 30%) is solid product.MS：202(M+H)。
Step 3. is with 2-pyridin-3-yl-pyrimidine-5-formic acid (110mg, 0.55mmol), I-hydroxybenzotriazole (83.5mg, 0.62mmol) and PS-DCC (568mg, 1.28mmol/g, 0.73mmol) mixture jolting 15min under room temperature in DMF (8mL), and adding aniline (34mg, 0.36mmol).In jolting under the room temperature after 18 hours, add the PS-triamine (436mg, 3.75mmol/g, 1.64mmol), and with this mixture jolting constantly at room temperature 18 hours.Cross filter solid and wash with DCM.Filtrate is concentrated, promptly 2-pyridin-3-yl-pyrimidine-5-formic acid phenyl amide(41.2mg, 41%) is solid product.MS：277(M+H)。
Embodiment 4
2-pyridine-2-base-pyrimidine-5-formic acid phenyl amide
Figure A20091013805300551
With 2-pyridine-2-base-pyrimidine-5-formic acid (100mg, 0.5mmol, according to the general method described in the step 1 and 2 of embodiment 2 preparation), I-hydroxybenzotriazole (76.1mg, 0.56mmol) and PS-DCC (518mg, 1.28mmol/g, 0.66mmol) jolting 15 minutes under room temperature of mixture in 8mL DMF, and add aniline (31mg, 0.33mmol).In jolting under the room temperature after 18 hours, add the PS-triamine (400mg, 3.75mmol/g, 1.5mmol), and with the jolting 18 hours continuously at room temperature of this mixture.Cross filter solid and wash with DCM.Filtrate is concentrated, promptly 2-pyridine-2-base-pyrimidine-5-formic acid phenyl amide(21mg, 23%) is solid product.MS：277(M+H)。
Embodiment 5
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide
Figure A20091013805300552
With 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (107mg, 0.49mmol, according to general method described in the step 1 and 2 of embodiment 2 preparation), I-hydroxybenzotriazole (75mg, 0.56mmol) and PS-DCC (511mg, 1.28mmol/g, 0.65mmol) the jolting 15min under room temperature of the mixture in DMF (8mL).Adding aniline (30.4mg, 0.33mmol).With the jolting 18 hours under room temperature of this mixture.Adding PS-triamine (392mg, 3.75mmol/g, 1.47mmol), and with the at room temperature continuous jolting of this mixture 18 hours.Cross filter solid and wash with EtOAc.Filtrate concentrated, promptly get certain yield 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide, be solid product.MS：294(M+H)。
Embodiment 6
2-(4-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide
Figure A20091013805300561
With 2-(4-fluoro-phenyl)-pyrimidine-5-formic acid (107mg, 0.49mmol, according to general method described in the step 1 and 2 of embodiment 2 preparation), I-hydroxybenzotriazole (75mg, 0.56mmol) and PS-DCC (511mg, 1.28mmol/g, 0.65mmol) the jolting 15min under room temperature of the mixture in DMF (8mL).Adding aniline (30.4mg, 0.33mmol).With the jolting 18 hours under room temperature of this mixture.Adding PS-triamine (392mg, 3.75mmol/g, 1.47mmol), and with the at room temperature continuous jolting of this mixture 18 hours.Filter out solid and wash with EtOAc.Filtrate is concentrated, promptly 2-(4-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide(83.4mg, 86%) is solid product.MS：294(M+H)。
Embodiment 7
2-(2-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide
Figure A20091013805300562
With 2-(2-fluoro-phenyl)-pyrimidine-5-formic acid (105mg, 0.48mmol, according to general method described in the step 1 and 2 of embodiment 2 preparation), I-hydroxybenzotriazole (74mg, 0.54mmol) and PS-DCC (501mg, 1.28mmol/g, 0.64mmol) the jolting 15min under room temperature of the mixture in DMF (8mL).Adding aniline (29.9mg, 0.32mmol).With the jolting 18 hours under room temperature of this mixture.Adding PS-triamine (385mg, 3.75mmol/g, 1.44mmol), and with the at room temperature continuous jolting of this mixture 18 hours.Filter out solid and wash with EtOAc.Filtrate is concentrated, promptly 2-(2-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide(60mg, 63%) is solid product.MS：294(M+H)。
Embodiment 8
2-phenyl-pyrimidine-5-formic acid (2,2-dioxo-2,3-dihydro-1H-2 λ * 6 * -benzo [c] isothiazole-5-yl)-acyl Amine
Figure A20091013805300571
With 2-phenyl-pyrimidine-5-formic acid (60mg, 0.3mmol), I-hydroxybenzotriazole (69mg, 0.51mmol) and PS-DCC (469mg, 1.21mmol/g, 0.6mmol) the jolting 60min under room temperature of the mixture in DMF (8mL).Add 2,2-dioxo 2,3-hydrogen-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine (55mg, 0.3mmol).With the jolting 2 days under room temperature of this mixture.Adding PS-triamine (221mg, 4.08mmol/g, 0.9mmol), and with the at room temperature continuous jolting of this mixture 18 hours.Filter out solid and wash with MeOH.Filtrate is concentrated, promptly 2-phenyl-pyrimidine-5- Formic acid (2,2-dioxo-2,3-dihydro-1H-2 λ * 6 * -benzo [c] isothiazole-5-yl)-acid amides(57mg), be solid product.MS:367 (M+H); 1H NMR (300MHz, CD 3OD): δ 4.58 (s, 2H), 6.86 (d, H), 7.53-7.65 (m, 4H), 7.76 (s, H), 8.46 (t, 2H), 9.33 (d, 2H), 10.41 (wide, H), 10.54 (s, H); IC 50=2.5nM.
Embodiment 9
2-phenyl-pyrimidine-5-formic acid [1-(1H-imidazoles-2-ylmethyl-piperidin-4-yl]-acid amides
Figure A20091013805300572
According to method similar to Example 8, but replace 2 with 1-(1H-imidazoles-2-ylmethyl)-piperidin-4-yl amine, 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes The 2-phenyl- Pyrimidine-5-formic acid [1-(1H-imidazoles-2-ylmethyl-piperidin-4-yl)-acid amides(74mg), be solid product.MS：363(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ1.80-1.89(m，2H)，2.05-2.16(m，2H)，3.21-3.37(m，2H)，3.50-3.60(m，2H)，4.14(m，H)，4.66(s，2H)，7.49-7.58(m，3H)，7.80(s，2H)，8.44(m，2H)，8.69(d，H)，9.23(s，2H)；IC 50＝2nM。
Embodiment 10
2-phenyl-pyrimidine-5-formic acid (6-dimethyl-amino-pyridine-3-ylmethyl)-acid amides
Figure A20091013805300581
According to method similar to Example 8, but replace 2 with 6-dimethylamino-pyridin-3-yl methylamine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid (6-dimethyl-amino-pyridine-3-ylmethyl)-acid amides, be solid product.MS：334(M+H)。
Embodiment 11
2-phenyl-pyrimidine-5-formic acid [2-(2-tetramethyleneimine-1-base-ethyl)-benzoxazoles-6-yl]-acid amides
Figure A20091013805300582
Step 1: DMF (45mL) solution of 2-methyl-6-nitro-benzoxazoles (30mmol), dimethylformamide dimethyl acetal (60mmol) and tetramethyleneimine (60mmol) was stirred 16 hours in 100 ℃.This reaction mixture is concentrated in a vacuum.Residue is dissolved in EtOAc, water and salt water washing, drying (Na 2SO 4) and filter.Filtrate is concentrated.With cold EtOAc wash residual thing, promptly The 6-nitro -2-(2-tetramethyleneimine-1-base-vinyl)-benzoEvil Azoles, be solid product. 1H NMR (300MHz, CDCl 3): δ 1.80-2.25 (wide, 4H), 3.10-3.80 (wide, 4H), 5.06 (d, H), 7.44 (d, H), 7.96 (d, H), 8.21 (m, 2H).
Step 2: with the hydrogenation 18 hours under 50psi pressure and room temperature of 6-nitro-2-(2-tetramethyleneimine-1-base-vinyl)-benzoxazoles (8.5mmol) and palladium/carbon (10%) ethanol (100mL) solution (0.85mmol).This mixture is filtered and filtrate is concentrated under vacuum, promptly 2-(2-tetramethyleneimine-1-base-ethene Base)-benzoEvil Azoles-6-base amine, be solid product. 1H NMR (300MHz, CDCl 3): δ 1.82 (m, 4H), 3.2 (wide, 4H), 3.65 (wide, 2H), 4.92 (d, H), 6.49 (d, H), 6.64 (d, H), 7.19 (d, H), 7.60 (d, H).
Step 3: MeOH (40mL) solution to 2-(2-tetramethyleneimine-1-base-vinyl)-benzoxazoles-6-base amine (3.2mmol) under room temperature adds sodium cyanoborohydride (6.4mmol).With reaction mixture refluxed heating 18 hours.This mixture is concentrated and residue is dissolved in DCM.Water and this solution of salt water washing, and dry (MgSO 4).In this solution, add a small amount of activated carbon, and filter this mixture.Filtrate is concentrated, promptly 2-(2-tetramethyleneimine-1-base-ethyl)-benzoEvil Azoles-6-base-amine, be solid product. 1H NMR (300MHz, CDCl 3): δ 1.79 (m, 4H), 2.61 (m, 4H), 3.00-3.18 (m, 4H), 4.78 (wide, 2N-H), 6.68 (q, H), 6.80 (d, H), 7.43 (d, H).
Step 4:, but replace 2,2-dioxo 2,3-dihydro-1H-2 λ with 2-(2-tetramethyleneimine-1-base-ethyl)-benzoxazoles-6-base amine (0.3mmol) according to method similar to Example 8 *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid [2-(2-tetramethyleneimine-1-base-ethyl)-benzoEvil Azoles-6-yl]- Acid amides, be solid product.MS:414 (M+H); 1H NMR (300MHz, DMSO-d 6): δ 1.70 (wide, 4H), 2.44-2.78 (m, 2H), 2.95-3.30 (m, 6H), 7.55-7.75 (m, 5H), 8.27 (s, H), 8.5 (q, 2H), 8.38 (s, 2H), 10.8 (s, H); IC 50=18nM.
Embodiment 12
2-phenyl-pyrimidine-5-formic acid 4-sulfamyl-benzyl acid amides
Figure A20091013805300591
According to method similar to Example 8, but replace 2 with 4-amino methyl-benzsulfamide (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-phonetic Pyridine-5-formic acid 4-sulfamyl-benzyl acid amides, be solid product.MS：369(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ4.60(d，2H)，7.34(s，2H)，7.54-7.64(m，5H)，7.78(d，2H)，8.45(m，2H)，9.30(s，2H)，9.46(t，H)。
Embodiment 13
2-phenyl-pyrimidine-5-formic acid [2-(4-sulfamyl-phenyl)-ethyl]-acid amides
Figure A20091013805300592
According to method similar to Example 8, but replace 2 with 4-(2-amino-ethyl)-benzsulfamide (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes The 2-phenyl- Pyrimidine-5-formic acid [2-(4-sulfamyl-phenyl)-ethyl]-acid amides, be solid product.MS：383(M+H)。
Embodiment 14
(R)-2-phenyl-pyrimidine-5-formic acid [4-(2-oxo-oxazolidines-4-ylmethyl)-phenyl]-acid amides
According to method similar to Example 8, but replace 2 with 4-(4-amino-benzyl)-oxazolidines-2-ketone (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes (R)-2-phenyl-pyrimidine-5-formic acid [4-(2-oxo-Evil Azoles alkane-4-ylmethyl)-phenyl]-acid amides, be solid product.MS：375(M+H)； 1H NMR(300MHz，CD3OD)：δ2.85-2.94(m，2H)，4.13-4.24(m，2H)，4.36(m，H)，7.30(d，2H)，7.46-7.60(m，3H)，7.70(d，2H)，8.44-8.56(m，2H)，9.23(d，2H)。
Embodiment 15
2-phenyl-pyrimidine-5-formic acid (6-acetylamino-pyridin-3-yl)-acid amides
Figure A20091013805300602
According to method similar to Example 8, but replace 2 with N-(5-amino-pyridine-2-yl)-ethanamide (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid (6-acetylamino-pyridin-3-yl)-acid amides, be solid product.MS：334(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.09(s，3H)，7.47-7.66(m，3H)，8.09(s，2H)，8.40-8.53(m，2H)，8.72(s，H)，9.36(s，2H)，10.29(s N-H)，10.70(s，N-H)。
Embodiment 16
2-phenyl-pyrimidine-5-formic acid (3-formamyl-phenyl)-acid amides
Figure A20091013805300611
According to method similar to Example 8, but replace 2 with 3-aminobenzamide (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-benzene pyridine-5- Formic acid (3-formamyl-phenyl)-acid amides, be solid product.MS：319(M+H)。
Embodiment 17
2-phenyl-pyrimidine-5-formic acid (3-methylamino formyl radical-phenyl)-acid amides
Figure A20091013805300612
According to method similar to Example 8, but replace 2 with 3-amino-N-methyl-benzamide (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes The 2-phenyl- Pyrimidine-5-formic acid (3-methylamino formyl radical-phenyl)-acid amides, be solid product.MS：333(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.79(d，3H)，7.47(t，H)，7.54-7.65(m，3H)，7.96(d，2H)，8.23(s，H)，8.37-8.54(m，3H)，9.37(s，2H)，10.70(s，1H)。
Embodiment 18
2-phenyl-pyrimidine-5-formic acid (4-hydroxyl-cyclohexyl)-acid amides
Figure A20091013805300613
According to method similar to Example 8, but replace 2 with 4-Trans-4-Amino Cyclohexanol (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5- Formic acid (4-hydroxy-cyclohexyl)-acid amides, be solid product.MS：298(M+H)。
Embodiment 19
4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-ethyl formate
Figure A20091013805300621
According to method similar to Example 8, but replace 2 with 2-amino-4-methyl-thiazole-5-ethyl formate (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-ethyl formate, be solid product.MS：369(M+H)。
Embodiment 20
2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-ethyl acetate
According to method similar to Example 8, but replace 2 with (2-amino-thiazolyl--4-yl)-ethyl acetate (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-ethyl acetate, be solid product.MS：369(M+H)。
Embodiment 21
4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-formic acid
Figure A20091013805300623
With 4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-ethyl formate (0.15mmol) and the mixture of the 10%NaOH aqueous solution (4mL) in THF (10mL) stirred 18 hours in 60 ℃.The evaporation THF and with 5% hcl acidifying residue to pH～2.0-2.5.Filter out precipitation and dry, promptly 4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-formic acid, be solid product.
MS：341(M+H)。
Embodiment 22
2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-acetate
Figure A20091013805300631
According to embodiment 21 similar methods, but with 2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl-ethyl acetate replaces 4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-ethyl formate, promptly make 2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-acetate, be solid product.
MS：341(M+H)。
Embodiment 23
2-phenyl-pyrimidine-5-formic acid 4-methyl sulfamyl-benzyl acid amides
According to method similar to Example 8, but replace 2 with 3-amino methyl-N-Methyl benzenesulfonyl amine hydrochlorate (1.5mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid 4-methyl sulfamyl-benzyl acid amides, be solid product.MS：383(M+H)； 1H NMR(300MHz，CD 3OD)：δ3.36(s，3H)，4.51(s，2H)，7.48-7.57(m，3H)，7.59(d，2H)，7.84(d，2H)，8.50(m，2H)，9.25(s，2H)。
Embodiment 24
2-phenyl-pyrimidine-5-formic acid 4-dimethylamino alkylsulfonyl-benzyl acid amides
(embodiment 12,0.3mmol), methyl iodide (0.3mmol) and the mixture of salt of wormwood (0.9mmol) in DMF (8mL) stirred 18 hours under room temperature with 2-phenyl-pyrimidine-5-formic acid sulfamyl-benzyl acid amides.This mixture is concentrated in a vacuum and residue is dissolved in EtOAc (30mL).With the solution with water that generates and salt water washing, drying (Na 2SO 4), filter and concentrate.With column chromatography purifying residue, with the DCM eluant solution of 5-10%EtOAc, promptly 2-phenyl-pyrimidine-5-formic acid 4-dimethylamino alkylsulfonyl-benzyl acid amides, be solid product.MS：397(M+H)； 1H NMR(300MHz，CD 3OD)：δ2.70(s，6H)，4.74(s，2H)，7.46-7.57(m，3H)，7.65(d，2H)，7.77(d，2H)，8.43-8.56(m，2H)，9.25(s，2H)。
Embodiment 25
2-phenyl-pyrimidine-5-formic acid (3,5-two fluoro-phenyl)-acid amides
Figure A20091013805300642
According to method similar to Example 8, but with 3,5-difluoroaniline (0.3mmol) replaces 2,2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5- Formic acid (3,5-two fluoro-phenyl)-acid amides, be solid product.MS：312(M+H)。
Embodiment 26
2-phenyl-pyrimidine-5-pyridine carboxylic acid-2-base acid amides
Figure A20091013805300643
According to method similar to Example 8, but replace 2 with 2-aminopyridine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid pyrrole Pyridine-2-base-acid amides, be solid product.MS：277(M+H)。
Embodiment 27
2-phenyl-pyrimidine-5-formic acid thiazol-2-yl acid amides
According to method similar to Example 8, but replace 2 with thiazolamine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid thiophene Azoles-2-base-acid amides, be solid product.MS：283(M+H)。
Embodiment 28
2-phenyl-pyrimidine-5-formic acid (3-sulfamyl-phenyl)-acid amides
According to method similar to Example 8, but replace 2 with 3-amino-benzsulfamide (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5- Formic acid (3-sulfamyl-phenyl)-acid amides, be solid product.MS：355(M+H)。
Embodiment 29
2-phenyl-pyrimidine-5-formic acid (2-oxo-1,2-dihydro-pyrimidine-4-yl)-acid amides
Figure A20091013805300653
According to method similar to Example 8, but replace 2 with 4-amino-1H-pyrimid-2-one (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-phonetic Pyridine-5-formic acid (2-oxo-1,2-dihydro-pyrimidin-4-yl)-acid amides, be solid product.MS：294(M+H)；
1H NMR(300MHz，DMSO-d 6)：δ7.17(bs，N-H)，7.47-7.68(m，4H)，7.90(d，H)，8.46(d，2H)，9.35(s，2H)，11.65(bs，N-H)；IC 50＝15nM。
Embodiment 30
2-phenyl-pyrimidine-5-formic acid (4-sulfamyl-phenyl)-acid amides
Figure A20091013805300661
According to method similar to Example 8, but replace 2 with 4-aminobenzene sulfonamide (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5- Formic acid (4-sulfamyl-phenyl)-acid amides, be solid product.MS：355(M+H)。IC 50＝5nM。
Embodiment 31
2-phenyl-pyrimidine-5-formic acid pyrimidine-4-base-acid amides
Figure A20091013805300662
According to method similar to Example 8, but replace 2 with 4-aminopyrimidine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid is phonetic Pyridine-4-base-acid amides, be solid product.MS：278(M+H)；
Embodiment 32
2-phenyl-pyrimidine-5-formic acid (1-pyridin-3-yl methyl-piperidin-4-yl)-acid amides
Figure A20091013805300663
According to method similar to Example 8, but replace 2 with 1-pyridin-3-yl methyl-piperidin-4-yl amine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid (1-pyridin-3-yl methyl-piperidin-4-yl)-acid amides, be solid product.MS：374(M+H)。
Embodiment 33
2-phenyl-pyrimidine-5-formic acid [2-(2-oxo-imidazolidine-1-yl)-ethyl]-acid amides
Figure A20091013805300671
According to method similar to Example 8, but replace 2 with 1-(2-amino-ethyl)-imidazolidin-2-one (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid [2-(2-oxo-imidazolidine-1-yl)-ethyl]-acid amides, be solid product.MS：312(M+H)； 1H NMR(300MHz，CDCl 3)：δ3.47-3.58(m，4H)，4.60-4.73(m，4H)，4.52(s，N-H)，7.46-7.57(m，3H)，8.02(bs，N-H)，8.53(m，2H)，9.24(s，2H)；IC 50＝32nM。
Embodiment 34
2-phenyl-pyrimidine-5-formic acid [2-(1H-imidazol-4 yl)-ethyl]-acid amides
Figure A20091013805300672
According to method similar to Example 8, but replace 2 with 2-(1H-imidazol-4 yl)-ethamine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes The 2-phenyl- Pyrimidine-5-formic acid [2-(1H-imidazol-4 yl)-ethyl]-acid amides, be solid product; MS:294 (M+H); IC 50=35nM.
Embodiment 35
2-phenyl-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-ylmethyl)-acid amides
Figure A20091013805300673
According to method similar to Example 8, but replace 2 with (tetrahydrochysene-pyrans-4-yl)-methylamine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-phonetic Pyridine-5-formic acid (tetrahydrochysene-pyrans-4-ylmethyl)-acid amides, be solid product.MS：298(M+H)。
Embodiment 36
2-phenyl-pyrimidine-5-formic acid (3-trifluoromethyl-phenyl)-acid amides
Figure A20091013805300681
According to method similar to Example 8, but replace 2 with 3-5-trifluoromethylaniline (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5- Formic acid (3-trifluoromethyl-phenyl)-acid amides, be solid product.MS：344(M+H)。
Embodiment 37
2-phenyl-pyrimidine-5-formic acid (2H-pyrazole-3-yl)-acid amides
Figure A20091013805300682
According to method similar to Example 8, but replace 2 with 2H-pyrazole-3-yl amine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5- Formic acid (2H-pyrazole-3-yl)-acid amides, be solid product.MS：266(M+H)。
Embodiment 38
2-phenyl-pyrimidine-5-formic acid (1-methyl-piperidin-4-yl)-acid amides
Figure A20091013805300683
According to method similar to Example 8, but replace 2 with 1-methyl-piperidin-4-yl amine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes The 2-phenyl-pyrimidine -5-formic acid (1-methyl-piperidin-4-yl)-acid amides, be solid product.MS：297(M+H)；IC 50＝96nM。
Embodiment 39
2-phenyl-pyrimidine-5-formic acid pyrimidine-2-base acid amides
According to method similar to Example 8, but replace 2 with 2-aminopyrimidine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid is phonetic Pyridine-2-base acid amides, be solid product.MS：278(M+H)。
Embodiment 40
2-(3,5-two fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides
Handle 2-(3 with diisopropylethylamine (0.09mL), 5-two fluoro-phenyl)-pyrimidine-5-formic acid (118mg, 0.5mmol, according to the preparation of the general method described in the step 1 and 2 of embodiment 2) and O-(7-azepine benzo triazol-1-yl)-N, N, N, N-tetramethyl-urea hexafluorophosphate (190mg, 0.5mmol) mixture in dry DMF (5mL), and under room temperature, stir 30min.Add 3-methyl sulfamyl benzylamine (150mg, the 0.75mmol) solution in dry DMF (1mL), and this mixture stirred 24 hours under room temperature.Except that desolvating and residue being distributed between EtOAc and water.Isolate organic phase and use saturated NaHCO 3, water and salt water washing, dry (MgSO 4), filter and concentrate in a vacuum.With column chromatography purifying residue, with the DCM eluant solution of 30%EtOAc, promptly 2-(3, the 5-difluorophenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides(125mg, 62%) is solid product.MS：419(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.41(d，3H)，4.64(d，2H)，7.43-7.75(m，5H)，7.80(s，1H)，8.05(d，2H)，9.37(s，2H)，9.60(t，1H)；IC 50＝49nM。
Embodiment 41
2-(2,5-two fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides
Figure A20091013805300701
Handle 2-(2 with the 0.09mL diisopropylethylamine, 5-two fluoro-phenyl)-pyrimidine-5-formic acid (118mg, 0.5mmol, according to the preparation of general method described in the step 1 and 2 of embodiment 2) and O-(7-azepine benzo triazol-1-yl)-N, N, N, N-tetramethyl-urea hexafluorophosphate (190mg, 0.5mmol) mixture in dry DMF (5mL), and under room temperature, stirred 30 minutes.Add 3-methyl sulfamyl benzylamine (150mg, the 0.75mmol) solution in dry DMF (1mL), and this mixture stirred 24 hours under room temperature.Remove desolvate and with residue at EtOAc and saturated NaHCO 3Between distribute.Isolate organic phase and water and salt water washing, dry (MgSO 4), filter and concentrate in a vacuum.With column chromatography purifying residue, with the DCM eluant solution of 20%EtOAc, promptly 2-(2,5-two fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides(135mg, 65%) is solid product.MS：419(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.41(d，3H)，4.64(d，2H)，7.43-7.78(m，5H)，7.89(s，1H)7.90(t，1H)，9.37(s，2H)，9.60(t，1H)。
Embodiment 42
2-(4-difluorophenyl)-4-methylpyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides
Figure A20091013805300702
Step 1: (1.25g, (0.17g in dehydrated alcohol 7.39mmol) (25mL) solution, and stirs 20min under room temperature 7.16mmol) to join sodium Metal 99.5 with 4-fluorine benzamidine hydrochloride.Adding ethyl-2-ethanoyl-3-(dimethylamino) acrylate (1.35g, 7.16mmol).With this mixture reflux 3 hours.Remove in a vacuum and desolvate.Residue is dissolved in EtOAc, water and salt water washing, drying (MgSO 4), filter and concentrate in a vacuum, promptly Ethyl-2-(4-fluorophenyl)-4-methyl-pyrimidine-5- Manthanoate(1.65g, 87%) is solid product.MS：261(M+H)261。
Step 2: handle ethyl-2-(4-fluorophenyl) pyrimidine-5-manthanoate (1.65g, 6.35mmol) solution in MeOH (75mL), and reflux 30min with 2N aqueous sodium hydroxide solution (10mL).Remove MeOH and water (50mL) dilution residue in a vacuum.With 2M hydrochloric acid the pH value of this solution is adjusted to～2.By filtering collecting precipitation, wash with water and vacuum-drying, promptly 2-(4-fluorine Phenyl)-4-methylpyrimidine-5-formic acid(1.3g, 88%) is solid product.MS：233(M+H)。
Step 3: handle 2-(4-fluorophenyl)-pyrimidine-5-formic acid (232mg with diisopropylethylamine (0.18mL), 1mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N, the mixture of N-tetramethyl-urea hexafluorophosphate (380mg 1 mmol) in dry DMF (12mL), and under room temperature, stir 30min.Add 3-methyl sulfamyl benzylamine (300mg, the 1.5mmol) solution in dry DMF (1.5mL), and this mixture stirred 24 hours under room temperature.Except that desolvating and residue being distributed between EtOAc and water.Isolate organic phase, use saturated NaHCO 3, water and salt water washing, dry (MgSO 4), filter and concentrate in a vacuum.With column chromatography purifying residue, with the n-heptane solution wash-out of 60%EtOAc, promptly 2-(4-fluorophenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides(210mg, 52%) is solid product.MS：415(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.42(s，3H)，2.63(s，3H)，4.60(d，2H)，7.37-7.40(t，2H)，7.50(s，1H)，7.60-7.75(m，3H)，7.80(s，1H)，8.45-8.50(dd，2H)，8.88(s，1H)，9.30(t，1H)。
Embodiment 43
2-(2-pyridyl)-pyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides
According to embodiment 40 similar methods, but replace 2-(3,5-two fluoro-phenyl)-pyrimidine-5-formic acid promptly to make with 2-(2-pyridyl)-pyrimidine-5-formate hydrochlorate 2-(2-pyridyl)-pyrimidine-5-formic acid 3-methyl ammonia Alkylsulfonyl-benzyl acid amides(183mg, 48%) is solid product.MS：384(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.42(d，3H)，4.64(d，2H)，7.46-7.54(m，1H)，7.51-7.70(m，4H)，7.80(s，1H)，8.00-8.07(t，1H)，8.44-8.50(d，1H)，8.80(d，1H)，9.37(s，2H)，9.55(t，1H)。
Embodiment 44
2-(3-pyridyl)-4-methylpyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides
Figure A20091013805300721
Handle 2-(3-pyridyl)-4-methylpyrimidine-5-formic acid (215mg with diisopropylethylamine (0.18mL), 1mmol, according to the preparation of the general method described in the step 1 and 2 of embodiment 42) and O-(7-azepine benzo triazol-1-yl)-N, N, N, N-tetramethyl-urea hexafluorophosphate (380mg, the 1mmol) mixture in dry DMF (12mL), and under room temperature, stir 30min.(355mg 1.5mmol), and stirred this mixture 24 hours under room temperature to add 3-methyl sulfamyl benzylamine hydrochloride.Remove desolvate and with residue at EtOAc and saturated NaHCO 3Between distribute.Isolate organic phase, water and salt water washing, dry (MgSO 4), filter and concentrate in a vacuum.With column chromatography purifying residue, with the EtOAc eluant solution of 2%MeOH, promptly 2-(3-pyridyl)-4-methyl-phonetic Pyridine-5-formic acid-3-methyl sulfamyl-benzyl acid amides(180mg, 45%) is solid product.MS：398(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.43(s，3H)，2.65(s，3H)，4.60(d，2H)，7.57-7.71(m，4H)，7.79(s，1H)，8.68-8.72(d，1H)，8.72-8.78(d，1H)，8.93(s，1H)，9.34(t，1H)，9.53(s，1H)。
The general method of embodiment 45 to 67
Figure A20091013805300731
General method X: the formation of sulphonamide
In a bottle, successively add amine H 2N-R ' (1mmol) and Dui diox (5mL) and piperidino-(1-position only) methylated polystyrene (375mg, 1.5mmol, 4mmol/g resin).This bottle is stirred 20min on a rail mounted jolting device.(181mg 0.9mmol) and with this reaction flask placed on the rail mounted jolting device jolting 18 hours to add 3-cyano group-benzene sulfonyl chloride.This bottle is removed from rail mounted jolting device, successively added MeOH (5mL) and 4-benzyloxy phenyl aldehyde polystyrene resin (100mg, 0.3mmol, 3mmol/g resin).On this rail mounted jolting device, continue to stir 5 hours.Filter this sample, wash this resin, and concentrate the organic moiety after merging, promptly get this sulfonamide compounds 1 with MeOH.
General method Y: the formation of sulphonamide
In a bottle, successively add amine H 2N-R ' (1mmol), Dui diox (5mL) and triethylamine (202mg, 2mmol).(181mg 0.9mmol), and placed on the rail mounted jolting device jolting 18 hours with this reaction flask to add 3-cyano group benzene sulfonyl chloride.Remove in a vacuum and desolvate.Residue is distributed between the 1N HCl aqueous solution (5mL) and EtOAc (10mL).Isolate organic phase, dry (Na 2SO 4), filter and concentrate in a vacuum, promptly get this sulfonamide compounds 1.
General method Z: hydrogenation
To sulfonamide compounds (0.9mmol) in the solution of MeOH (9mL), successively add carbon carry palladium (200mg, 10wt% carbon carries, 50wt% water, ACROS) and the dense HCl aqueous solution (1mL).Allow this reaction alternately react 3 cycles in a vacuum and in the hydrogen (1atm), in hydrogen atmosphere, use magnetic stirrer 24 hours then.Should react and filtrate be concentrated in a vacuum with diatomite filtration, promptly get this amine hydrochlorate compound 2.
General method W: parallel acidylate
To 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (196mg, 0.9mmol) in the solution of DCM (5mL), successively add oxalyl chloride (229mg, 1.8mmol) and DMF (2 μ L).Stir this reaction 3 hours.Add dry toluene (0.5mL) and this mixture is concentrated in a vacuum.Residue is dissolved in EtOAc (7mL), and the solution that generates is added in the bottle under quick agitation condition, wherein contain this amine hydrochlorate compound 2 (1mmol), Na 2CO 3(212mg) and the mixture of water (5mL).Stir this reaction 18h, isolate organic phase and concentrated in a vacuum.Residue is suspended among the DMSO (3mL), filters,, promptly get required product through reversed-phase HPLC purifying (water and acetonitrile are moving phase, add the 0.1%TFA damping fluid again).
Embodiment 45
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-ethyl sulfamyl-benzyl acid amides
Figure A20091013805300741
In an ice-water bath, cool off ethamine (2M, in MeOH, DCM 6mmol) (40mL) solution, and add 3-cyano group-benzene sulfonyl chloride (402mg, 2mmol).Stir this reaction 2 hours apace.Add entry (40mL), and add dense HCl carefully reaction is acidified to about pH 4.Remove DCM in a vacuum.By filtering collecting precipitation.To precipitate hydrogenation with general method Z, promptly get this amine hydrochlorate compound.With this amine hydrochlorate compound of process for acylating W acidylate, promptly make 2-(3-fluoro-benzene Base)-pyrimidine-5-formic acid 3-ethyl sulfamyl-benzyl acid amides(449mg), be solid product.MS：415(M+H)； 1H NMR(300MHz，CDCl 3)：δ＝0.95(t，3H)，2.75-2.9(m，2H)，4.65(d，2H)，7.47(t，1H)，7.55-7.75(m，4H)，7.81(s，1H)，8.17(d，1H)，8.32(d，1H)，9.27(bs，1H)，9.35(s，2H)，9.58(t，1H)；IC 50＝58nM。
Embodiment 46
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-oxyethyl group-ethyl sulfamyl)-benzyl acid amides
Figure A20091013805300751
According to general method Y, Z and W, but use 2-oxyethyl group-ethamine, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-oxyethyl group-ethyl sulfamyl)-benzyl acid amides(210mg), for Powdered.MS：457(M-H)； 1H NMR(300MHz，CDCl 3)：δ1.0(t，3H)，2.9(t，2H)，4.6(s，2H)，7.45(t，1H)，7.5-7.7(m，4H)，7.8(s，1H)，8.16(d，1H)，8.31(d，1H)，9.3(s，1H)。
Embodiment 47
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxyl-propyl group sulfamyl)-benzyl acid amides
Figure A20091013805300752
According to general method Y, Z and W, but use 1-amino-propane-2-alcohol, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxyl-propyl group sulfamyl)-benzyl acid amides(265mg), be solid product.MS：443(M-H)； 1H NMR(300MHz，CDCl 3)：δ0.97(d，3H)，2.57-2.71(m，2H)，3.55-3.61(q，1H)，4.6(s，2H)，7.45(t，1H)，7.54-7.77(m，4H)，7.8(s，1H)，8.16(d，1H)，8.31(d，1H)，9.34(s，2H)。
Embodiment 48
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-cyclopropyl sulfamyl-benzyl acid amides
Figure A20091013805300761
According to general method Y, Z and W, but use cyclopropylamine, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-cyclopropyl sulfamyl-benzyl acid amides(265mg), be solid product.MS：425(M-H)； 1H NMR(300MHz，CDCl 3)：δ0.35-0.49(m，4H)，2.07-2.14(m，1H)，4.65(d，2H)，7.46(dt，1H)，7.57-7.73(m，4H)，7.81(s，1H)，7.94(d，1H)，8.16(d，1H)，8.31(d，1H)，9.33(s，2H)，9.55(t，1H)；IC 50＝132nM。
Embodiment 49
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-hydroxyl-propyl group sulfamyl)-benzyl acid amides
According to general method Y, Z and W, but use the 3-aminopropanol, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-hydroxyl-propyl group sulfamyl)-benzyl acid amides(175mg), for Powdered.MS:443 (M-H); 1H NMR (300MHz, CDCl 3): δ 1.51 (p, 2H), 2.79 (t, 2H), CH 2Be hidden among the water peak, 4.64 (s, 2H), 7.45 (dt, 1H), 7.55-7.70 (m, 4H), 7.79 (s, 1H), 8.135 (d, 1H), 8.31 (d, 1H), 9.29 (s, N-H), 9.33 (s, 1H); IC 50=22nM.
Embodiment 50
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-methoxyl group-ethyl sulfamyl)-benzyl acid amides
Figure A20091013805300771
According to general method Y, Z and W, but use the 2-methoxyethyl amine, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-methoxyl group-ethyl sulfamyl)-benzyl acid amides(190mg), for Powdered.MS:443 (M-H); 1H NMR (300MHz, CDCl 3): δ 2.90 (t, 2H), 3.14 (s, 3H), CH 2Be hidden among the water peak, 4.63 (s, 2H), 7.45 (dt, 1H), 7.54-7.71 (m, 4H), 7.80 (s, 1H), 8.15 (d, 1H), 8.31 (d, 1H), 9.33 (s, 2H), 9.57 (bs, N-H).
Embodiment 51
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-methoxyl group-propyl group sulfamyl)-benzyl acid amides
Figure A20091013805300772
According to general method Y, Z and W, but use the 3-METHOXY PROPYL AMINE, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-methoxyl group-propyl group sulfamyl)-benzyl acid amides(201mg), for Powdered.MS：457(M-H)； 1H NMR(300MHz，CDCl 3)：δ1.57(p，2H)，2.77(t，2H)，3.13(s，3H)，3.24(t，2H)，4.63(s，2H)，7.45(dt，1H)，7.55-7.70(m，4H)，7.79(s，1H)，8.15(d，1H)，8.31(d，1H)，9.33(s，2H)，9.58(bs，N-H)；IC 50＝37nM。
Embodiment 52
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(4-methoxyl group-butyl sulfamyl)-benzyl acid amides
Figure A20091013805300781
According to general method Y, Z and W, but use the 4-methoxybutyl amine, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(4-methoxyl group-butyl sulfamyl)-benzyl acid amides(220mg), for Powdered.MS:471 (M-H); 1H NMR (300MHz, CDCl 3): δ 1.01 (t, 2H), 1.57 (p, 2H), 2.78 (t, 2H), CH 2And CH 3Be hidden among the water peak, 4.63 (s, 2H), 7.45 (dt, 1H), 7.55-7.70 (m, 4H), 7.79 (s, 1H), 8.16 (d, 1H), 8.31 (d, 1H), 9.33 (s, 2H), 9.59 (bs, N-H).
Embodiment 53
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-cyclohexyl sulfamyl-benzyl acid amides
Figure A20091013805300782
According to general method Y, Z and W, but use cyclo-hexylamine, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-cyclohexyl sulfamyl-benzyl acid amides(240mg), for Powdered.MS：467(M-H)； 1H NMR(300MHz，CDCl 3)：δ1.07(t，6H)，1.41(bs，1H)，1.53-1.55(m，4H)，2.90(bs，1H)，4.63(d，2H)，7.45(dt，1H)，7.53-7.72(m，4H)，7.80(s，1H)，8.15(dd，1H)，8.30(d，1H)，9.33(s，2H)，9.55(t，1H)。
Embodiment 54
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxyl-1,1-dimethyl-ethyl sulfamyl)-benzyl acid amides
Figure A20091013805300791
According to general method Y, Z and W, but use 2-amino-2-methyl-propane-1-alcohol, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxyl-1,1-dimethyl-ethyl ammonia Alkylsulfonyl)-the benzyl acid amides(90mg), be solid product.MS：457(M-H)； 1H NMR(300MHz，CDCl 3)：δ1.00(s，6H)，3.19(d，2H)，4.63(d，2H)，4.75(t，1H)，7.35(s，1H)，7.45(dt，1H)，7.52-7.67(m，3H)，7.75(d，1H)，7.84(s，1H)，8.16(d，1H)，8.31(d，1H)，9.33(s，2H)，9.54(t，1H)；IC 50＝60nM。
Embodiment 55
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-sulfamyl-benzyl acid amides
Figure A20091013805300792
According to general method Y, Z and W, but use TERTIARY BUTYL AMINE, promptly make as the amine among the method Y 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-sulfamyl-benzyl acid amides(25mg), for Powdered.MS：385(M-H)； 1H NMR(300MHz，CDCl 3)：δ4.62(d，2H)，7.38(s，1H)，7.45(t，1H)，7.53-7.75(m，5H)，7.83(s，1H)，8.16(d，1H)，8.32(d，1H)，8.34(s，1H)，9.32(s，2H)，9.55(t，1H)；IC 50＝31nM。
Embodiment 56
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-morpholine-4-base-ethyl sulfamyl)-benzyl acid amides
Figure A20091013805300801
According to general method X, Z and W, but use 2-morpholine-4-base-ethamine, promptly make as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-morpholine-4-base-ethyl sulfamyl)-benzyl Acid amides(150mg), it contains a spot of TFA.MS：500(M+H)； 1H NMR(300MHz，CDCl 3)：δ3.0-3.4(m，8H)，3.5-3.75(m，2H)，3.85-4.1(m，2H)，4.64(d，2H)，7.45(dt，1H)，7.60-7.75(m，4H)，7.82(s，1H)，8.01(s，1H)，8.16(d，1H)，8.30(d，1H)，9.33(s，2H)，9.56(t，1H)，9.69(m，1H)；IC 50＝37nM。
Embodiment 57
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-piperidines-1-base-ethyl sulfamyl)-benzyl acid amides
Figure A20091013805300802
According to general method X, Z and W, but use 2-piperidines-1-base ethamine, promptly make as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-piperidines-1-base-ethyl sulfamyl)-benzyl Acid amides(125mg), it contains a spot of TFA.MS：498(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.2-1.8(m，6H)，2.8-2.95(m，2H)，3.11(bs，4H)，3.3-3.5(m，2H)，4.64(d，2H)，7.46(dt，1H)，7.60-7.75(m，4H)，7.82(s，1H)，8.00(bs，1H)，8.16(d，1H)，8.31(d，1H)，9.08(m，1H)，9.33(s，2H)，9.56(t，1H)。
Embodiment 58
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(1-methyl-tetramethyleneimine-2-yl)-ethyl sulfamyl]-benzyl Acid amides
Figure A20091013805300811
According to general method X, Z and W, but use 2-(1-methyl-tetramethyleneimine-2-yl)-ethamine, promptly make as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(1-methyl-tetramethyleneimine-2-yl)- The ethyl sulfamyl]-the benzyl acid amides(110mg).MS：498(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.4-1.7(m，2H)，1.7-2.2(m，4H)，2.7-2.9(m，5H)，3.0-3.1(m，1H)，3.1-3.3(m，1H)，3.4-3.6(m，1H)，4.64(d，2H)，7.46(dt，1H)，7.58-7.72(m，4H)，7.79(s，1H)，8.16(d，1H)，8.31(d，1H)，9.33(s，2H)，9.56(t，1H)。
Embodiment 59
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(1-ethyl-tetramethyleneimine-2-ylmethyl)-sulfamyl]-the benzyl acyl Amine
According to general method X, Z and W, but use C-(1-ethyl-tetramethyleneimine-2-yl)-methylamine, promptly make as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(1-ethyl-tetramethyleneimine-2-base Methyl)-sulfamyl]-the benzyl acid amides(85mg), it contains a spot of TFA.MS：498(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.20(t，3H)，1.6-2.2(m，4H)，2.95-3.2(m，4H)，3.25-3.45(m，2H)，3.45-3.6(m，1H)，4.65(d，2H)，7.46(dt，1H)，7.60-7.76(m，4H)，7.83(s，1H)，8.09-8.17(m，2H)，8.31(d，1H)，9.13(bs，1H)，9.34(s，2H)，9.57(t，1H)。
Embodiment 60
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(1H-imidazol-4 yl)-ethyl sulfamyl]-the benzyl acid amides
Figure A20091013805300821
According to general method X, Z and W, but use 2-(1H-imidazol-4 yl)-ethamine, promptly make as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(1H-imidazol-4 yl)-ethyl sulphonamide Base]-the benzyl acid amides(30mg), be solid product.MS：481(M+H)； 1H NMR(300MHz，CDCl 3)：δ2.77(t，2H)，3.06(t，2H)，4.63(d，2H)，7.40(s，1H)，7.46(t，1H)，7.56-7.96(m，4H)，7.77(s，1H)，7.86(t，1H)，8.16(d，1H)，8.31(d，1H)，9.32(s，2H)，9.55(t，1H)；IC 50＝61nM。
Embodiment 61
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[3-(2-methyl-piperidines-1-yl)-propyl group sulfamyl]-the benzyl acyl Amine
According to general method X, Z and W, but use 3-(2-methyl-piperidines-1-yl)-propylamine, promptly make as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[3-(2-methyl-piperidines-1-yl)-propyl group Sulfamyl]-the benzyl acid amides(155mg), it contains a spot of TFA.MS：526(M+H)； 1HNMR(300MHz，CDCl 3)：δ1.19(dd，3H)，1.3-1.9(m，8H)，2.75-3.25(m，6H)，3.3-3.6(m，1H)，4.64(d，2H)，7.46(dt，1H)，7.58-7.72(m，4H)，7.79-7.85(m，2H)，8.16(d，1H)，8.31(d，1H)，8.9-9.2(m，1H)，9.34(s，2H)，9.57(t，1H)。
Embodiment 62
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-tetramethyleneimine-1-base-propyl group sulfamyl)-benzyl acid amides
Figure A20091013805300831
According to general method X, Z and W, but use 3-tetramethyleneimine-1-base propylamine, promptly make as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-tetramethyleneimine-1-base-propyl group sulfamyl)- The benzyl acid amides(105mg).MS：498(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.7-1.9(m，4H)，1.9-2.1(m，2H)，2.8-3.0(m，4H)，3.05-3.15(m，2H)，3.2-3.35(m，2H)，4.64(d，2H)，7.46(dt，1H)，7.58-7.77(m，4H)，7.79(m，1H)，8.16(d，1H)，8.31(d，1H)，9.34(s，2H)，9.41(bs，1H)，9.56(t，1H)。
Embodiment 63
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-dimethylamino-ethyl sulfamyl)-benzyl acid amides
Figure A20091013805300832
According to general method X, Z and W, but use N 1, N 1-dimethyl-ethane-1, the 2-diamines promptly makes as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-dimethylamino-ethyl ammonia sulphur Acyl group)-the benzyl acid amides(38mg), be solid product.MS：458(M+H)； 1H NMR(300MHz，CDCl 3)：δ2.78(s，6H)，3.0-3.2(m，4H)，4.65(d，2H)，7.46(dt，1H)，7.60-7.76(m，4H)，8.01(t，1H)，8.16(d，1H)，8.31(d，1H)，9.33(bs，3H)，9.56(t，1H)；IC 50＝45nM。
Embodiment 64
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-diethylamino-ethyl sulfamyl)-benzyl acid amides
Figure A20091013805300841
According to general method X, Z and W, but use N 1, N 1-diethyl-ethane-1, the 2-diamines promptly makes as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-diethylamino-ethyl ammonia sulphur Acyl group)-the benzyl acid amides(128mg), it contains a spot of TFA.MS：486(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.16(t，6H)，3.0-3.2(m，8H)，4.65(d，2H)，7.46(dt，1H)，7.60-7.76(m，4H)，7.83(s，1H)，8.02(t，1H)，8.16(d，1H)，8.31(d，1H)，9.17(bs，1H)，9.33(s，2H)，9.57(t，1H)。
Embodiment 65
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-dimethylamino-2,2-dimethyl-propyl group sulfamyl)-benzyl The base acid amides
Figure A20091013805300842
According to general method X, Z and W, but use 2,2, N 1, N 1-tetramethyl--propane-1, the 3-diamines promptly makes as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-dimethylamino-2,2- Dimethyl-propyl group sulfamyl)-the benzyl acid amides(190mg), it contains a spot of TFA.MS：500(M+H)； 1H NMR(300MHz，CDCl 3)：δ0.95(s，6H)，2.68(d，2H)，2.84(d，6H)，3.03(d，2H)，4.64(d，2H)，7.46(dt，1H)，7.58-7.74(m，4H)，7.80(s，1H)，7.85(t，1H)，8.16(d，1H)，8.31(d，1H)，8.85(bs，1H)，9.34(s，2H)，9.57(t，1H)；IC 50＝35nM。
Embodiment 66
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(5-dimethylamino-amyl group sulfamyl)-benzyl acid amides
Figure A20091013805300851
According to general method X, Z and W, but use N 1, N 1-dimethyl-pentane-1, the 5-diamines promptly makes as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(5-dimethylamino-amyl group ammonia Alkylsulfonyl)-the benzyl acid amides(175mg).MS：500(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.22-1.27(m，2H)，1.34-1.44(m，2H)，1.44-1.57(m，2H)，2.70-2.74(m，8H)，2.92-2.99(m，2H)，4.63(d，2H)，7.46(dd，1H)，7.56-7.70(m，4H)，7.78(s，1H)，8.16(d，1H)，8.31(d，1H)，9.33(s，2H)，9.56(t，1H)。
Embodiment 67
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-diisopropylaminoethyl-ethyl sulfamyl)-benzyl acid amides
Figure A20091013805300852
According to general method X, Z and W, but use N 1, N 1-di-isopropyl-ethane-1, the 2-diamines promptly makes as the amine among the method X 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-diisopropylaminoethyl-ethyl Sulfamyl)-the benzyl acid amides(150mg).MS：514(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.21(t，12H)，3.06-.308(m，4H)，3.58-3.65(m，2H)，4.64(d，2H)，7.46(dd，1H)，7.60-7.75(m，4H)，7.82(s，1H)，8.07(t，1H)，8.16(d，1H)，8.31(d，1H)，9.34(s，2H)，9.59(t，1H)。
Embodiment 68
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-(methylsulfonyl amino-methyl)-benzyl acid amides
Figure A20091013805300861
Step 1. is with Na 0(0.66g 28.6mmol) joins among the anhydrous EtOH (100mL) and under room temperature and stirs 15min.Add 3-fluorine benzamidine hydrochloride (4.87g, 27.8mmol) and stir this solution 15min.Add 2-dimethylamino methylene-3-oxo-ethyl butyrate (5.3g, 28.6mmol), and with this reaction mixture at N 2Reflux is 1 hour in the atmosphere.Reaction is cooled to room temperature and concentrated in a vacuum.Residue is dissolved in EtOAc (300mL), with salt water washing (2x100mL), dry (Na 2SO 4), filter and concentrate, promptly 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-ethyl formate(6.8g, 99%).MS：261(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.43(t，J＝7.0Hz，3H)，2.92(s，3H)，4.42(q，J＝7.0Hz，2H)，7.24(m，1H)，7.45(m，1H)，8.27(m，1H)，8.37(m，1H)，9.21(s，1H)。
Step 2. with 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-ethyl formate (6.7g, 27.2mmol) and NaOH (2.1g is reflux 45min in the solution of 1: 1: 1 THF, MeOH and water (300mL) in ratio 54.4mmol).Evaporation THF/MeOH handles this aqueous solution with 3N HCl the pH value is adjusted between 2 and 3.Filter out solid product, wash with water and dry in a vacuum, promptly 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid(5.4g, 91%) is solid product.MS：233(M+H)； 1H NMR(300MHz，CD 3OD)：δ2.85(s，3H)，7.24(m，1H)，7.50(m，1H)，8.17(m，1H)，8.32(m，1H)，9.20(s，1H)。
Step 3. to 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid (0.195g, add in THF 0.89mmol) (5mL) solution carbonyl dimidazoles (0.18g, 1.1mmol), and in 60 ℃ the heating 2 hours.This mixture is cooled to room temperature.Adding (3-amino methyl-benzyl)-t-butyl carbamate (0.25mL, 1.1mmol), and with this mixture stirring 12 hours.Dilute this mixture with EtOAc (100mL),, use Na with salt water washing (2x50mL) 2SO 4Dry, filtration and concentrated in a vacuum.With flash chromatography method purifying residue, with 20%-80%EtOAc/ heptane wash-out, promptly get [ 3-({ [2-(3-fluoro-phenyl)-4- Methyl-pyrimidine-5-carbonyl]-amino }-methyl)-benzyl]-t-butyl carbamate(0.32g, 80%) is solid product.MS：451(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ1.38(s，9H)，2.65(s，3H)，4.14(d，J＝6.1Hz，2H)，4.50(d，J＝5.6Hz，2H)，7.15(m，1H)，7.24(m，1H)，7.31(m，1H)，7.43(m，1H)，7.62(m，1H)，8.13(m，1H)，8.28(m，1H)，8.89(s，1H)，9.23(m，1H)。
Step 4. in 0 ℃ to [3-({ [2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino }-methyl)-benzyl]-t-butyl carbamate (0.05g, 0.111mmol) DCM (2mL) solution in add TFA (0.013mL, 0.111mmol), and with this mixture stirring 2.5 hours.This mixture is concentrated in a vacuum.Residue is dissolved in THF (2mL).Add Et 3N (0.05mL, 0.333mmol) and methylsulfonyl chloride (0.010mL 0.133mmol), and stirred this mixture 12 hours.Dilute this mixture with EtOAc (100mL), use saturated NH 4Cl (2x50mL) solution washing is used Na 2SO 4Dry, filtration, and concentrate in a vacuum.With flash chromatography method purifying residue, with 20%-80%EtOAc/ heptane wash-out, promptly 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-(methylsulfonyl amino-methyl)- The benzyl acid amides(0.03g, 64%) is for Powdered.MS：429(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.65(s，3H)，2.86(s，3H)，4.18(d，J＝6.3Hz，2H)，4.50(d，J＝5.9Hz，2H)，7.27-7.45(m，3H)，7.62(m，2H)，8.13(m，1H)，8.28(m，1H)，8.90(s，1H)，9.25(m，1H)；IC 50＝48.5nM。
Embodiment 69
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-[(propane-2-sulfuryl amino)-methyl]-the benzyl acid amides
According to (the similar method of step 3), but replace (3-amino methyl-benzyl)-t-butyl carbamate with different third SULPHURYL CHLORIDE (0.57mmol) promptly makes with embodiment 68 2-(3-fluoro-phenyl)-4-methyl-pyrimidine -5-formic acid 3-[(propane-2-sulfuryl amino)-methyl]-the benzyl acid amides(100mg), be solid product.MS：456(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ1.22(d，J＝6.8Hz，6H)，2.65(s，3H)，3.10(m，1H)，4.18(d，J＝6.2Hz，2H)，4.51(s，2H)，7.27-7.45(m，3H)，7.62(m，2H)，8.14(m，1H)，8.26(m，1H)，8.90(s，1H)，9.25(m，1H)。
Embodiment 70
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-methyl sulfamyl methyl-benzyl acid amides
Figure A20091013805300881
Step 1: use Na 2SO 3(1.3g, H 10.3mmol) 2O (50mL) solution-treated 3-brooethyl-benzonitrile (2g, EtOH 10.2mmol) (50mL) solution, and reflux 4 hours.This mixture is concentrated in a vacuum.Residue is suspended among DCM (100mL) and the DMF (1mL), and also (8mL 43.4mmol) handles with oxalyl chloride to be cooled to 0 ℃.Warm this mixture is to room temperature and stirred 3 hours.Dilute this mixture with salt solution,, use Na with DCM (2x100mL) extraction 2SO 4Dry, filtration, and concentrate in a vacuum.Residue is dissolved in THF (25mL), add methylamine (2M, 12.5mL, 25mmol) and stirred this mixture 12 hours.This mixture with EtOAc (100mL) dilution, is used saturated NH 4Cl (2x100mL) solution washing is used Na 2SO 4Dry, filtration, and concentrate in a vacuum.With flash chromatography method purifying residue, with 20%-80%EtOAc/ heptane wash-out, promptly C-(3-cyano group-phenyl)-N-methyl-Toluidrin(1.5g, 69%) is for Powdered.MS：209(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.60(d，J＝4.8Hz，3H)，4.44(s，2H)，7.02(m，1H)，7.61(m，1H)，7.74(m，1H)，7.85(m，2H)。
Step 2: (42mg, THF 0.2mmol) (4mL) solution adds BH to C-(3-cyano group-phenyl)-N-methyl-Toluidrin 3The THF of THF (1M, 1mL) solution.Seal this mixture and in 100 ℃ in 120 seconds of a microwave reactor internal reaction.This mixture is poured among the 1M HCl (20mL), alkalized to pH～10,, use Na with DCM (2x50mL) extraction with 3M NaOH 2SO 4Dry, filtration and concentrated in a vacuum, promptly C-(3-amino methyl-phenyl)-N-methyl-Toluidrin, the latter need not to be further purified and promptly is directly used in next step.
Step 3: according to (the similar method of step 3), but replace (3-amino methyl-benzyl)-t-butyl carbamate with C-(3-amino methyl-phenyl)-N-methyl-Toluidrin (2.3mmol) promptly makes with embodiment 68 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-methyl sulfamyl methyl-benzyl acid amides(30mg), be solid product.MS：429(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.58(d，J＝4.8Hz，3H)，2.65(s，3H)，4.34(s，2H)，4.53(d，J＝5.7Hz，2H)，6.92(m，1H)，7.27-7.45(m，3H)，7.62(m，2H)，8.14(m，1H)，8.28(m，1H)，8.90(s，1H)，9.23(m，1H)。
Embodiment 71
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-(sec.-propyl sulfamyl-methyl)-benzyl acid amides
Step 1: (2g adds Na in EtOH 10.2mmol) (50mL) solution to 3-brooethyl-benzonitrile 2SO 3(1.3g, H 10.3mmol) 2O (50mL) solution, and with this mixture reflux 4 hours.This mixture is concentrated in a vacuum.Residue is suspended among DCM (100mL) and the DMF (1mL), and also (4.5mL 24.4mmol) handles with oxalyl chloride to be cooled to 0 ℃.Allow this mixture be warmed to room temperature 3 hours.(100mL) dilutes this mixture with salt solution, with DCM (2x100mL) extraction, uses Na 2SO 4Dry, filtration, and concentrate in a vacuum.Residue is dissolved in THF (100mL), and (3.5mL handles 40.8mmol) with Isopropylamine.Stir this mixture 12h,, use saturated NH with EtOAc (200mL) dilution 4Cl (2x100mL) solution washing is used Na 2SO 4Dry, filtration, and concentrate in a vacuum.With flash chromatography method purifying residue, with 20%-80%EtOAc/ heptane wash-out, promptly C-(3-cyano group-phenyl)-N-sec.-propyl-Toluidrin, for Powdered.MS：237(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ1.10(d，J＝6.6Hz，6H)，3.36(m，1H)，4.42(s，2H)，7.09(m，1H)，7.57(m，1H)，7.74(m，1H)，7.85(m，2H)。
Step 2: (0.5g adds BH in THF 2.06mmol) (10mL) solution to C-(3-cyano group-phenyl)-N-sec.-propyl-Toluidrin 3The THF of THF (1M, 10.3mL) solution.Seal this mixture and in 100 ℃ in 120 seconds of a microwave reactor internal reaction.This mixture is poured among the 1M HCl (50m L), alkalized to pH～10,, use Na with the DCM extraction with 3M NaOH 2SO 4Dry, filtration and concentrated in a vacuum, promptly C-(3-amino methyl-phenyl)-N-sec.-propyl-Toluidrin, the latter need not to be further purified and promptly is directly used in next step.
Step 3: according to embodiment 68 (the similar method of step 3), but use C-(3-amino methyl-phenyl)-N- Sec.-propyl-Toluidrin(2mmol) replace (3-amino methyl-benzyl)-t-butyl carbamate, promptly make 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-[(propane-2-sulfuryl amino)-methyl]-the benzyl acid amides(160mg), be solid product.MS：457(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ1.09(d，J＝6.4，6H)，2.65(s，3H)，3.37(m，1H)，4.31(s，2H)，4.53(d，J＝5.8，2H)，6.99(d，J＝7.1Hz，1H)，7.27-7.45(m，3H)，7.62(m，1H)，8.13(m，1H)，8.28(m，1H)，8.90(s，1H)，9.24(m，1H)；IC 50＝34nM。
Embodiment 72
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(methylsulfonyl amino-methyl)-benzyl acid amides
Figure A20091013805300901
Step 1. to 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid(0.5g, add in THF 2.25mmol) (25mL) solution carbonyl dimidazoles (0.5g, 2.7mmol), and in 60 ℃ the heating 2 hours.This mixture is cooled to room temperature and add (3-amino methyl-benzyl)-t-butyl carbamate (0.67mL, 2.7mmol).Stir this mixture 12h,,, use Na with salt water washing (2x50mL) with EtOAc (100mL) dilution 2SO 4Dry, filtration and concentrated in a vacuum.With flash chromatography method purifying residue, with 20%-80%EtOAc/ heptane wash-out, promptly [3-({ [2-(3-fluoro-phenyl)-pyrimidine-5-carbonyl]-ammonia Base }-methyl)-benzyl]-t-butyl carbamate(0.8g, 80%) is solid product.MS：437(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ1.35(s，9H)，4.13(d，J＝6.1Hz，2H)，4.54(d，J＝5.9Hz，2H)，7.27-7.48(m，4H)，7.62(m，1H)，8.16(m，1H)，8.31(m，1H)，9.32(s，2H)，9.43(m，1H)。
(0.28g adds HCl De diox (6.5mL, 4N) solution, and stirred this mixture 2.5 hours in 0.64mmol) to step 2. to [3-({ [2-(3-fluoro-phenyl)-pyrimidine-5-carbonyl]-amino }-methyl)-benzyl]-t-butyl carbamate in 0 ℃.This mixture is concentrated in a vacuum.Residue is dissolved in DCM (3mL), and adds Et 3N (0.21mL, 0.1.5mmol) and methylsulfonyl chloride (0.105mL, 0.1.3mmol).Stirred this mixture 12 hours, and, used saturated NH with EtOAc (100mL) dilution 4Cl (2x50mL) solution washing is used Na 2SO 4Dry, filtration, and concentrate in a vacuum.With flash chromatography method purifying residue, with 20%-80%EtOAc/ heptane wash-out, promptly 2-(3-fluoro-phenyl)- Pyrimidine-5-formic acid 3-(methylsulfonyl amino-methyl)-benzyl acid amides(0.25g, 94%) is for Powdered.MS：459(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.85(s，3H)，4.17(d，J＝6.2Hz，2H)，4.56(d，J＝5.9Hz，2H)，7.27-7.62(m，5H)，8.17(m，1H)，8.32(m，1H)，9.32(s，2H)，9.45(m，1H)。
Embodiment 73
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(propane-2-sulfuryl amino)-methyl]-the benzyl acid amides
According to the similar method of embodiment 72 (step 2), but, promptly make with different propane SULPHURYL CHLORIDE (1.3mmol) replacement methylsulfonyl chloride 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-[(propane-2-alkylsulfonyl Amino)-methyl]-the benzyl acid amides(7mg), be solid product.MS：443(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ1.20(d，J＝6.8Hz，6H)，3.05(m，1H)，4.17(d，J＝6.4Hz，2H)，4.55(d，J＝5.9Hz，2H)，7.27-7.62(m，5H)，8.17(m，1H)，8.32(m，1H)，9.32(s，2H)，9.45(m，1H)。
Embodiment 74
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl methyl-benzyl acid amides
According to (the similar method of step 1), but replace (3-amino methyl-benzyl)-t-butyl carbamate with C-(3-amino methyl-phenyl)-N-methyl-Toluidrin (1.17mmol) promptly makes with embodiment 72 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl methyl-benzyl acid amides(105mg), be solid product.MS：415(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.57(d，J＝4.8Hz，3H)，4.32(s，2H)，4.57(d，J＝5.9Hz，2H)，6.92(m，1H)，7.28-7.67(m，5H)，8.17(m，1H)，8.32(m，1H)，9.32(s，2H)，9.46(m，1H)。
Embodiment 75
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(sec.-propyl sulfamyl-methyl)-benzyl acid amides
Figure A20091013805300922
According to (the similar method of step 1), but replace (3-amino methyl-benzyl)-t-butyl carbamate with C-(3-amino methyl-phenyl)-N-sec.-propyl-Toluidrin (1.45mmol) promptly makes with embodiment 72 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(sec.-propyl sulfamyl-methyl)-benzyl acid amides(140mg), be solid product.MS：443(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ1.07(d，J＝6.4，6H)，3.39(m，1H)，4.29(s，2H)，4.56(d，J＝5.9，2H)，6.99(d，J＝7.1Hz，1H)，7.28-7.45(m，3H)，7.62(m，1H)，8.17(m，1H)，8.32(m，1H)，9.32(s，2H)，9.45(m，1H)。
Embodiment 76
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (2-methylsulfonyl amino-pyridine-4-ylmethyl)-acid amides
Figure A20091013805300931
Step 1: with 2-amino-different cigarette nitrile (isonicotinonitrile) (1g, 8.4mmol) and methylsulfonyl chloride (0.716mL, 9.2mmol) solution in pyridine (10mL) stirred 12 hours under room temperature.This mixture is poured on ice and stirs 20min.Filter this mixture and water (100mL) and diethyl ether (100mL) washing successively.Dry in a vacuum this solid, promptly N-(4-cyanopyridine-2-yl)-methylsulfonyl Amine(1.1g, 66%).MS：198(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ3.32(s，3H)，7.27(s，1H)，7.48(d，J＝5.1Hz，1H)，8.53(d，J＝5.3Hz，1H)。
Step 2: with N-(4-cyano group-pyridine-2-yl)-Toluidrin (0.15g 0.76mmol) is dissolved among MeOH (4mL) and the dense HCl (2mL), and with Pd/C (10%, 150mg) handle.With this mixture at H 2Stir 12 hours, filtration and concentrated in a vacuum in the atmosphere, promptly N-(4-amino methyl-pyridine-2- Base)-Toluidrin(0.15g, 97%), the latter need not to be further purified and promptly is directly used in next step.
Step 3: according to (the similar method of step 1), but replace (3-amino methyl-benzyl)-t-butyl carbamate with N-(4-amino methyl-pyridine-2-yl)-Toluidrin (0.75mmol) promptly makes with embodiment 72 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (2-methylsulfonyl amino-pyridine-4-ylmethyl)-acid amides(320mg), be solid product.MS：402(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ3.24(s，3H)，4.53(d，J＝5.7Hz，2H)，6.97(s，br，2H)，7.43(m，1H)，7.63(m，1H)，8.18(m，2H)，8.33(m，1H)，9.33(s，2H)，9.52(m，1H)。
Embodiment 77
2-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides
Figure A20091013805300941
Step 1. under room temperature to 2-methyl sulfane base-pyrimidine-5-methyl-formiate 1 (1g, add in DCM 5.43mmol) (60mL) solution in batches MCPBA (2.81g, 16.29mmol).The solution that generates stirred under room temperature spend the night.Add Na 2S 2O 3Water (1.6g) (60mL) solution.This mixture is stirred 20min under room temperature.Layering is also used DCM (2x20mL) aqueous layer extracted.Use saturated NaHCO 3DCM layer after (3x20mL) solution washing merges, dry (Na 2SO 4), filter and concentrate in a vacuum, promptly 2-methylsulfonyl-pyrimidine-5-methyl-formiate, be solid product (1.05g, 90%).MS：217(M+H)； 1H NMR(300MHz，CDCl 3)：δ3.41(s，3H)，4.06(s，3H)，9.44(s，2H)。
(2.5g, DCM 11.56mmol) (30mL) solution add tetrabutyl ammonium cyanide (3.1g, water 11.56mmol) (30mL) solution to step 2. lentamente to 2-methylsulfonyl-pyrimidine-5-methyl-formiate 2 under room temperature.Stir this mixture 80min.With this mixture water (2x20mL) washing, dry (Na 2SO 4), filter and concentrate in a vacuum.With column chromatography purifying residue, with 5%-60%EtOAc/ heptane wash-out, promptly 2-cyano group-pyrimidine-5-methyl-formiate(1.16g, 61%) is solid product.MS：164(M+H)； 1H NMR(300MHz，CDCl 3)：δ4.05(s，3H)，9.37(s，2H)。
Step 3. under room temperature to 2-cyano group-pyrimidine-5-methyl-formiate 3 (1g, MeOH 6.13mmol) (20mL) solution add hydroxy amine hydrochloric acid salt (0.64g, 9.2mmol) and sodium acetate (0.76g, 9.2mmol).With the mixture reflux that generates 2 hours.This mixture is cooled to room temperature and concentrated in a vacuum.Add water (30mL) to residue, filter this solid, and wash with water twice.Spend the night at this solid of vacuum oven, promptly 2-(N-hydroxy formamidine base)-pyrimidine-5-methyl-formiate(1.09g, 91%) is solid product.MS：197(M+H)。
Step 4. to 2-(N-hydroxy formamidine base)-pyrimidine-5-methyl-formiate (900mg, dripping acetyl chloride in pyridine 4.59mmol) (15mL) solution (432mg, 5.5mmol).The solution that generates was stirred under room temperature 1 hour, and reflux 3h.This solution is cooled to room temperature and concentrated in a vacuum.Add water (30mL) to residue, and extract this mixture with EtOAc (3x20mL).Use saturated NaHCO 3Organic layer after washing merges, dry (Na 2SO 4), filter and concentrate in a vacuum, promptly 2-(5-first Base-[1,2,3]Evil Diazole-3-yl)-pyrimidine-5-methyl-formiate(900mg, 89%) is solid product.MS：221(M+H)。
Step 5. is in 0 ℃ of water (20mL) solution that adds LiOH (100mg) in MeOH (20mL) solution of 2-(5-methyl-[1,2,4] oxadiazole-3-yls)-pyrimidine-5-methyl-formiate (900mg).Remove ice bath, with this mixture restir 10min.Evaporating solvent adds entry (20mL).(2x20mL) washs this aqueous solution with ether, is acidified to pH～3 with 2N HCl.With the sedimentation and filtration that generates, wash with water and in vacuum drying oven dried overnight, promptly 2-(5-methyl-[1,2,4]Evil Diazole-3-yl)-pyrimidine-5-formic acid(350mg, 37%) is solid product.MS：207(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.73(s，3H)，9.39(s，2H)。
Step 6. under room temperature to 2-(5-methyl-[1,2,4] oxadiazole-3-yl)-pyrimidine-5-formic acid (50mg, 0.24mmol) DCM (10mL) solution in add 1-[3-(dimethylamino) propyl group-3-ethyl carbodiimide (50mg, 0.26mmol) and the N-hydroxybenzotriazole (35mg, 0.26mmol).Stir this mixture 10min, and adding tetrahydrochysene-pyrans-4-base amine (27mg, 0.26mmol).This mixture stirring is spent the night, successively use 2N HCl (1x5mL), saturated NaHCO3 (1x5mL), water (1x5mL) washing, dry (Na 2SO 4), filter and concentrate in a vacuum.With column chromatography purifying residue, with the DCM eluant solution of 5%MeOH, promptly 2-(5-methyl-[1,2,4]Evil Diazole-3-yl)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides(33mg), be solid product.MS：290(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.70(m，2H)，2.04(m，2H)，2.76(s，3H)，3.59(m，2H)，4.06(m，2H)，4.28(m，1H)，9.26(s，2H)；IC 50＝513.5nM。
Embodiment 78
2-(5-methyl-[1,2,4]Evil Diazole-3-yl)-pyrimidine-5-formic acid 4-sulfamyl-benzamide
Figure A20091013805300961
According to (the similar method of step 6), but replace tetrahydrochysene-pyrans-4-base amine with 4-amino methyl-benzsulfamide promptly makes with embodiment 77 2-(5-methyl-[1,2,4]Evil Diazole-3-yl)-pyrimidine-5-formic acid 4- Sulfamyl-benzamide, be solid product.MS：375(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.72(s，3H)，4.61(d，2H)，7.33(s，2H)，7.56(d，2H)，7.80(d，2H)，9.39(s，2H)。
Embodiment 79
2-(5-methyl-[1,2,4]Evil Diazole-3-yl)-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acyl Amine
Figure A20091013805300962
According to (the similar method of step 6), but replace tetrahydrochysene-pyrans-4-base amine with 3-phenyl-[1,2,4] thiadiazoles-5-base amine promptly makes with embodiment 77 2-(5-methyl-[1,2,4]Evil Diazole-3-yl)-pyrimidine-5- Formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amides, be solid product.MS：366(M+H)； 1HNMR(300MHz，DMSO-d 6)：δ2.74(s，3H)，7.56(m，3H)，8.24(m，2H)，9.63(s，2H)。
Embodiment 80
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(morpholine-4-alkylsulfonyl)-benzyl acid amides
Figure A20091013805300963
According to method similar to Example 5, but replace aniline, promptly make with 3-(morpholine alkylsulfonyl)-benzylamine 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(morpholine-4-alkylsulfonyl)-benzyl acid amides, be solid product.MS：457(M+H)； 1H NMR(300MHz，CDCl 3)：δ2.88-3.10(m，4H)，3.65-3.85(m，4H)，4.78(d，2H)，6.88-7.05(bs，N-H)，7.18-7.35(m，H)，7.40-7.60(m，2H)，7.60-7.80(m，3H)，8.10-8.35(q，4H)，9.21(s，2H)。
Embodiment 81
2-phenyl-pyrimidine-5-formic acid 3,4-dimethoxy-benzyl acid amides
According to method similar to Example 8, but with 3,4-dimethoxy-benzylamine (0.3mmol) replaces 2,2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes The 2-phenyl-pyrimidine -5-formic acid 3,4-dimethoxy-benzyl acid amides, be solid product.MS：350(M+H)。
Embodiment 82
2-phenyl-pyrimidine-5-formic acid (2-benzo [1,3] dioxole-5-base-ethyl)-acid amides
According to method similar to Example 8, but replace 2,2-dioxo 2,3-dihydro-1H-2 λ with 2-benzo [1,3] dioxole-5-base ethylamine hydrochloride (0.3mmol) *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid (2-benzo [1,3] dioxole-5-base-ethyl)- Acid amides, be solid product.MS：348(M+H)； 1H NMR(300MHz，CDCl 3)：δ2.91(t，2H)，3.74(m，2H)，5.98(s，2H)，6.20(bs，N-H)，6.65-6.83(m，3H)，7.54(m，3H)，8.49(m，2H)，9.08(s，2H)；IC 50＝2nM。
Embodiment 83
2-phenyl-pyrimidine-5-formic acid (1H-indazole-5-yl)-acid amides
Figure A20091013805300981
According to method similar to Example 8, but replace 2 with 1H-indazole-5-amine (0.3mmol), 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5- Formic acid (1H-indazole-5-yl)-acid amides, be solid product.MS：316(M+H)； 1H NMR(300MHz，CDCl 3)：δ6.99(d，H)，7.06(q，H)，7.52-7.63(m，4H)，8.10(s，H)，8.38(d，H)，8.57(m，3H)，9.53(s，H)；IC 50＝23nM。
Embodiment 84
2-phenyl-pyrimidine-5-formic acid 4-[1,2,3] thiadiazoles-5-yl)-the benzyl acid amides
Figure A20091013805300982
According to method similar to Example 8, but use 4-[1,2,3] thiadiazoles-5-base benzylamine (0.3mmol) replacement 2,2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes The 2-phenyl- Pyrimidine-5-formic acid 4-[1,2,3] thiadiazoles-5-yl)-the benzyl acid amides, be solid product.MS：374(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ4.25(d，2H)，7.52-7.60(m，5H)，8.12(d，2H)，8.45(m，2H)，9.31(s，2H)，9.46(bs，N-H)，9.59(s，H)；IC 50＝6.5nM。
Embodiment 85
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides
Figure A20091013805300983
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with 3-amino methyl-N-methyl-benzsulfamide hydrochloride with 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acyl Amine, be solid product.MS：415(M+H)； 1H NMR(300MHz，CDCl 3)：δ2.73(s，3H)，4.72(d，2H)，6.70(bs，N-H)，7.15-7.26(m，H)，7.41-7.65(m，3H)，7.77(d，H)，7.85(s，N-H)，8.15(d，H)，8.24(d，H)，9.76(s，H)。IC 50＝106nM。
Embodiment 86
4-methyl-2-pyridine-2-base-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides
Figure A20091013805300991
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with 3-amino methyl-N-methyl-benzsulfamide with 4-methyl-2-pyridine-2-base-pyrimidine-5-formic acid 4-methyl-2-pyridine-2-base-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides, be solid product.MS：398(M+H)； 1H NMR(300MHz，CDCl 3)：δ2.54(s，3H)，2.59(s，3H)，4.62(d，2H)，7.23-7.42(m，3H)，7.48-7.60(m，H)，7.61-7.68(d，H)，7.78-7.93(m，2H)，8.37-8.44(d，H)，8.51-8.62(m，H)，8.67(s，H)。
Embodiment 87
2-phenyl-pyrimidine-5-formic acid 4-morpholine-4-base benzyl acid amides
According to method similar to Example 8, but replace 2 with 4-morpholine-4-base-benzylamine, 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid 4- Morpholine-4-base benzyl acid amides, be solid product.MS：375(M+H)； 1H NMR(300MHz，CDCl 3)：δ3.18(t，4H)，3.88(t，4H)，4.62(d，2H)，6.48(bs，N-H)，6.92(m，2H)，7.29(m，2H)，7.47-7.58(m，3H)，8.50(m，2H)，9.16(s，2H)；IC 50＝12nM。
Embodiment 88
6-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1H-benzimidazolyl-2 radicals-methyl-formiate
Figure A20091013805301001
According to method similar to Example 8, but replace 2 with 6-amino-1H-benzimidazolyl-2 radicals-methyl-formiate, 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes The 6-[(2-phenyl -pyrimidine-5-carbonyl)-amino]-1H-benzimidazolyl-2 radicals-methyl-formiate, be solid product.MS：374(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ3.95(s，3H)，7.52-7.63(m，5H)，7.70-7.82(m，H)，8.29(s，H)，9.38(s，2H)，10.68(d，H)。
Embodiment 89
6-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1H-benzimidazolyl-2 radicals-formic acid
With 6-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-(1: 1: 1,60mL) solution in stirred under room temperature and spends the night at MeOH/ water/tetrahydrofuran (THF) for 1H-benzimidazolyl-2 radicals-methyl-formiate (0.44mmol) and LiOH (4.40mmol).MeOH and THF are evaporated in a vacuum, and the mixture in the water is acidified to pH～2 with 5%HCl.Filter the precipitation that generates, water (10mL) washing is also dry, promptly 6-[(2- Phenyl-pyrimidine-5-carbonyl)-amino]-1H-benzimidazolyl-2 radicals-formic acid, be solid product (115mg).MS：360(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ7.52-7.70(m，5H)，8.30(s，H)，8.48(m，3H)，9.28(S，H)，9.38(s，2H)，10.73(s，N-H)。
Embodiment 90
2-phenyl-pyrimidine-5-formic acid (cumarone-5-ylmethyl)-acid amides
Figure A20091013805301011
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with C-cumarone-5-base methylamine with 2-phenyl-pyrimidine-5-formic acid 2-phenyl-phonetic Pyridine-5-formic acid (cumarone-5-ylmethyl)-acid amides, be solid product.MS：330(M+H)； 1HNMR(300MHz，CDCl 3)：δ4.79(d，2H)，6.58(bs，N-H)，6.78(m，H)，7.32(q，H)，7.49-7.56(m，4H)，7.64(s，H)，7.66(d，2H)，8.48(m，2H)，9.18(s，2H)；IC 50＝7nM。
Embodiment 91
2-phenyl-pyrimidine-5-formic acid 4-methylsulfonyl amino-benzyl acid amides
Figure A20091013805301012
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with N-(4-amino methyl-phenyl)-Toluidrin with 2-phenyl-pyrimidine-5-formic acid 2- Phenyl-pyrimidine-5-formic acid 4-methylsulfonyl amino-benzyl acid amides, be solid product.MS：383(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.96(s，3H)，4.89(d，2H)，7.18(d，2H)，7.33(d，2H)，7.51-7.63(m，3H)，78.43(m，2H)，8.27(s，2H)，9.36(bs，N-H)。
Embodiment 92
2-phenyl-pyrimidine-5-formic acid 4-formamyl-benzyl acid amides
Figure A20091013805301021
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with 4-amino methyl-benzamide with 2-phenyl-pyrimidine-5-formic acid 2-phenyl-phonetic Pyridine-5-formic acid 4-formamyl-benzyl acid amides, be solid product.MS：333(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ4.59(d，2H)，7.32(s，N-H)，7.43(d，2H)，7.50-7.63(m，4H)，7.85(d，2H)，7.94(s，H)，8.47(m，2H)，9.37(s 2H)，9.43(t，N-H)；IC 50＝16nM。
Embodiment 93
2-phenyl-pyrimidine-5-formic acid 3-(2-hydroxyl-ethyl sulfamyl)-benzyl acid amides
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with 3-amino methyl-N-(2-hydroxyethyl)-benzsulfamide hydrochloride with 2-phenyl-pyrimidine-5-formic acid 2-phenyl-pyrimidine-5-formic acid 3-(2-hydroxyl-ethyl sulfamyl)-benzyl acid amides, be solid product.MS：413(M+H)；1H NMR(300MHz，CD 3OD)：δ2.96(t，2H)，3.53(t，2H)，4.78(d，2H)，7.42-7.91(m，9H)，8.46(m，2H)，9.22(s，2H)，9.40(bs，N-H)。
Embodiment 94
2-phenyl-pyrimidine-5-formic acid 4-(morpholine-4-alkylsulfonyl)-benzyl acid amides
Figure A20091013805301031
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with 4-(morpholine-4-alkylsulfonyl)-benzylamine hydrochloride with 2-phenyl-pyrimidine-5-formic acid (0.35mmol) 2-phenyl-pyrimidine-5-formic acid 4-(morpholine-4-alkylsulfonyl)-benzyl acid amides, be solid product.MS：439(M+H)； 1H NMR(300MHz，CD 3OD)：δ2.96(t，4H)，3.70(t，4H)，4.73(s，2H)，7.53(m，3H)，7.65(d，2H)，7.77(d，2H)，8.49(d，2H)，9.26(s，2H)。
Embodiment 95
2-phenyl-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides
Figure A20091013805301032
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with 3-amino methyl-N-methyl-benzsulfamide hydrochloride with 2-phenyl-pyrimidine-5-formic acid 2-phenyl-pyrimidine-5-formic acid 3-methyl sulfamyl benzyl acid amides, be solid product.MS：383(M+H)； 1H NMR(300MHz，CD 3OD)：δ2.53(s，3H)，4.71(s，2H)，7.26(m，H)，7.46-7.80(m，7H)，7.87(s，H)，8.49(m，2H)，9.24(s，2H)。
Embodiment 96
2-phenyl-pyrimidine-5-formic acid [2-(2-amino-4-methyl-thiazole-5-yl)-ethyl]-acid amides
Figure A20091013805301033
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and (2-amino-ethyl-thiazol-2-yl amine two hydrobromates replace aniline, promptly make with 5-with 2-phenyl-pyrimidine-5-formic acid (0.12mmol) 2-phenyl-pyrimidine-5-formic acid [2-(2-amino-4-methyl-thiazole-5-yl)-second Base]-acid amides, be solid product.MS：340(M+H)； 1H NMR(300MHz，CDCl 3)：δ2.11(s，3H)，2.92(t，2H)，3.61(q，2H)，6.70(bs，N-H)，7.40-7.58(m，3H)，8.37-8.54(m，2H)，9.12(s，2H)。
Embodiment 97
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides
Figure A20091013805301041
Step 1: (40wt%, flask 7.5mmol) cools off in ice-water bath, uses magnetic stirrer simultaneously will to fill DCM (90mL) and aqueous methylamine solution.(5g 2.49mmol), and adds DCM (10mL) to wash the material that is attached on the flask walls to add 3-cyano group benzene sulfonyl chloride.After the 30min, add the dense HCl aqueous solution in 0 ℃ and become acidity (pH＜4) until reaction.Add entry (50mL) and remove DCM in a vacuum.Filtered residue, promptly 3-cyano group-N-methyl-benzsulfamide, be solid product (99%).MS:195 (M+H); 1H NMR (300MHz, CDCl 3): δ 2.76 (d, 3H), 4.48 (wide-s, N-H), 7.7 (t, 1H), 7.9 (d, 1H), 8.13 (d, 1H), 8.19 (s, 1H).
Step 2: to 3-cyano group-N-methyl-benzsulfamide (4.88g, MeOH 2.49mmol) (160mL) solution successively add the dense HCl aqueous solution (16mL) and carbon carry palladium (10wt%, 50wt% water, 1.6g).Use magnetic stirrer, allow this reaction alternately carry out 3 circulations in a vacuum with in the 1 normal atmosphere hydrogen (balloon), in 1 normal atmosphere hydrogen, stir this reaction 2 days then.With diatomite filtration should the reaction, and add fresh carbon carry palladium (10wt%, 50wt% water, 1.6g).In 1 normal atmosphere hydrogen, stirred this reactant 24 hours.Should react with diatomite filtration, and filtrate was concentrated in a vacuum, promptly 3-amino methyl-N-methyl-benzsulfamide hydrochloride, be solid product (99%).MS:201 (M+H); 1H NMR (300MHz, DMSO-d6): δ 2.41 (d, 3H), 4.12 (d, 2H), 7.23-7.57 (m, 2H), 7.70 (d, 1H), 7.81 (d, 1H), 8.49 (wide-s, 3H).
Step 3: to 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (545mg, successively add 2.5mmol) and in the mixture of DCM (35mL) oxalyl chloride (635mg, 5mmol) and DMF (20 μ L).Under room temperature, stir this reaction 3 hours.Add dry toluene (10mL) and this reaction mixture is concentrated in a vacuum.Residue is dissolved in EtOAc (30mL).With the solution that generates in 0 ℃ join 3-amino methyl-N-methyl-benzsulfamide hydrochloride (590mg, 2.5mmol), (530mg is 5mmol) and in the mixture of water (10mL) for yellow soda ash.Allow the reaction mixture that generates be warmed to room temperature and stir and spend the night.Remove about 80% EtOAc in a vacuum, and add heptane to be settled out product.By filtering collecting precipitation, and in EtOAc recrystallization twice, promptly 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl ammonia Alkylsulfonyl-benzyl acid amides(400mg).Mother liquor is concentrated and, promptly get another part with flash chromatography method purifying residue 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides(130mg), for Powdered.MS：401(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.41(d，3H)，4.64(d，2H)，7.42-7.50(m，2H)，7.57-7.70(m，4H)，7.78(s，1H)，8.16(d，1H)，8.31(d，1H)，9.33(s，2H)，9.53(t，1H)。IC 50＝9.5nM。
Embodiment 98
4-{[(2-phenyl-pyrimidine-5-carbonyl)-amino]-benzyl }-diethyl phosphonate
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with (4-amino-benzyl)-diethyl phosphonate with 2-phenyl-pyrimidine-5-formic acid (4-{[(2- Phenyl-pyrimidine-5-carbonyl)-amino]-methyl }-benzyl)-diethyl phosphonate, be solid product.MS：426(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.13(t，3H)，1.32(t，3H)，3.79(q，H)，3.99(q，H)，4.20(m，2H)，5.91(q，4.62(d，H)，7.27(d，3H)，7.48(s，3H)，7.67(d，2H)，8.42(d，2H)，9.28(s，H)，9.53(s，H)；IC 50＝38nM。
Embodiment 99
4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-butyl)-diethyl phosphonate
Figure A20091013805301061
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with (the amino butyl of 4-)-diethyl phosphonate oxalate with 2-phenyl-pyrimidine-5-formic acid 4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-butyl }-diethyl phosphonate, be solid product.MS：392(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.31(t，6H)，1.77(m，6H)，3.48(q，2H)，3.97-4.19(m，4H)，7.40-7.58(m，3H)，7.84(bs，N-H)，8.40-8.57(m，2H)，9.23(s，2H)；IC 50＝23.5nM。
Embodiment 100
4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-ethyl)-diethyl phosphonate
Figure A20091013805301062
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with (4-amino-ethyl)-diethyl phosphonate oxalate with 2-phenyl-pyrimidine-5-formic acid 4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-ethyl }-diethyl phosphonate, be solid product.MS：364(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.38(t，6H)，2.16(m，2H)，3.78(m，2H)，4.03-4.22(m，4H)，7.50(m，3H)，8.09(bs，N-H)，8.48(m，2H)，9.24(s，2H)。
Embodiment 101
Phenyl-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-methyl)-diethyl phosphonate
Figure A20091013805301071
According to method similar to Example 5, but replace 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid, and replace aniline, promptly make with (amino-phenyl-methyl)-diethyl phosphonate hydrochloride with 2-phenyl-pyrimidine-5-formic acid { phenyl-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-methyl }-diethyl phosphonate, be solid product.MS：426(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.13(t，3H)，1.32(t，3H)，3.70-3.90(m，H)，3.90-4.08(m，H)，4.09-4.31(m，2H)，5.88(q，H)，7.27(m，3H)，7.47(m，3H)，7.65(d，H)，8.43(m，2H)，9.27(s，2H)，9.35(d，N-H)；IC 50＝48nM。
Embodiment 102
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methylsulfonyl)-the benzyl acid amides
Figure A20091013805301072
According to method similar to Example 5, but replace aniline, promptly make with 3-methylsulfonyl-benzylamine 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methylsulfonyl)-the benzyl acid amides, be solid product.MS：386(M+H)； 1H NMR(300MHz，CD 3OD)：δ3.12(s，3H)，4.93(d，2H)，7.24-7.37(m，H)，7.48-7.70(m，2H)，7.77(d，H)，7.88(d，H)，7.98(s，H)，8.20(d，H)，8.34(d，H)，9.25(S，2H)。
Embodiment 103
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (1-methylsulfonyl-piperidines-3-ylmethyl) acid amides
Figure A20091013805301081
Step 1: add 2-(the 3-fluoro-phenyl)-pyrimidine-solution of 5-formyl chloride (4.65mmol) in ethyl acetate (20mL) in the solution in ethyl acetate (30mL) and water (20mL) to salt of wormwood (13.94mmol) and 3-amino methyl-piperidines-1-t-butyl formate (4.65mmol).Under room temperature, stir this mixture overnight.With this reaction mixture ethyl acetate extraction, wash dry (Na with water 2SO 4) and concentrate in a vacuum, promptly 3-({ [2-(3-fluoro-phenyl)-pyrimidine-5-carbonyl]-amino }-methyl)-piperidines-1-formic acid uncle fourth Ester, be solid product.MS 415(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.47(s，9H)，1.55-2.22(m，5H)，2.90-4.90(m，6H)，7.15-7.25(m，H)，7.41-7.53(m，H)，7.56(bs，NH)，8.18(d，H)，8.29(d，H)，9.21(s，2H)。
Step 2: hydrogen chloride gas is blasted DCM (20mL) solution of 3-({ [2-(3-fluoro-phenyl)-pyrimidine-5-carbonyl]-amino }-methyl)-piperidines-1-t-butyl formate (3.76mmol), and under room temperature, stir this reaction 2 hours.This mixture is concentrated in a vacuum, promptly 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (piperidines-3- Ylmethyl)-amide hydrochloride, be solid product.MS 415(M+H)； 1H NMR(300MHz，CD 3OD)：δ1.22-1.50(m，2H)，1.68-1.90(m，H)，1.90-2.06(bs，2H)，2.06-2.17(bs，6H)，2.73-3.04(m，2H)，3.24-3.50(m，H)，7.24-7.35(m，H)，7.48-7.60(m，H)，8.19(d，H)，8.34(d，H)，9.23(s，2H)。
Step 3: with methylsulfonyl chloride (0.523mmol) in 0 ℃ add to be stirred 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (piperidines-3-ylmethyl)-amide hydrochloride (0.523mmol) and DCM (20mL) solution of triethylamine (2.62mmol).Stirred this mixture one hour in 0 ℃, under room temperature, stir then and spend the night.Wash (20mL) this reaction mixture with water.With organic layer separation, dry (MgSO 4), filter and concentrate in a vacuum.With the silica gel chromatography residue, use the EtOAc wash-out, promptly 2-(3-fluoro-benzene Base)-pyrimidine-5-formic acid (1-methylsulfonyl-piperidines-3-ylmethyl)-acid amides, be solid product.MS：393(M+H)； 1H NMR(300MHz，CD 3OD)：δ1.43-1.95(m，4H)，2.10-2.23bs，H)，3.04-3.50(m，5H)，3.60-3.78(m，H)，6.71-6.90(bs，N-H)，7.18-7.23(m，H)，7.42-7.57(m，H)，8.18-8.37(q，2H)，9.20(s，2H)。
Embodiment 104
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (1-dimethylamino alkylsulfonyl-piperidines-3-ylmethyl)-acid amides
Figure A20091013805301091
With dimethylamino SULPHURYL CHLORIDE (0.632mmol) in 0 ℃ of DCM (20mL) solution that joins 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (piperidines-3-ylmethyl)-acid amides tri hydrochloride (0.632mmol) in the stirring and triethylamine (3.16mmol).Stirred this mixture one hour in 0 ℃, under room temperature, stir then and spend the night.Dilute this reaction mixture with DCM (10mL), and wash (30mL) with water.Isolate organic layer, dry (Na 2SO 4), filter and concentrate in a vacuum.Residue is ground with EtOAc, promptly 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (1-dimethylamino alkylsulfonyl-piperidines-3-Ji Jia Base)-acid amides(245mg), be solid product.MS：422(M+H)； 1H NMR(300MHz，CDCl 3)：δ1.37-1.69(m，2H)，1.74-1.92(m，2H)，2.03-2.17(bs，H)，2.81(s，6H)，3.09-3.20(m，H)，3.21-3.50(m，4H)，3.60-3.75(m，H)，6.83-6.98(bs，N-H)，7.16-7.28(m，H)，7.42-7.55(m，H)，8.16-8.33(q，2H)，9.20(s，2H)。
Embodiment 105
2-(phenyl)-pyrimidine-5-formic acid 3-methylsulfonyl amino-benzyl acid amides
Figure A20091013805301092
(embodiment 115,0.526mmol) and DCM (20mL) solution of triethylamine (1.05mmol) with the 2-phenyl-pyrimidine-5-formic acid 3-amino-benzyl acid amides of methylsulfonyl chloride (0.553mmol) in 0 ℃ add to be stirred.Under room temperature, stirred this mixture one hour.Extract with the 5%HCl termination reaction and with DCM (20mL).Isolate organic layer, water (20mL) and salt solution (20mL) washing, dry (Na 2SO 4), filter and concentrate in a vacuum.With silica gel column chromatography purifying residue, with the DCM eluant solution of 0-5%MeOH, promptly 2-(phenyl)-pyrimidine-5-formic acid 3-methylsulfonyl amino-benzyl The base acid amides(200mg), be solid product.MS：383(M+H)； 1H NMR(300MHz，CDCl 3)：δ3.41(s，3H)，4.76-4.72(m，2H)，7.00(bs，N-H)，7.05-7.23(m，2H)，7.27-7.60(m，5H)，8.40-8.53(m，2H)，9.16(s，2H)。
Embodiment 106
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-ethanoyl sulfamyl-benzyl acid amides
Solution in EtOAc (10mL) and water (10mL) adds 2-(the 3-fluoro-phenyl)-pyrimidine-solution of 5-formyl chloride (1.22mmol) in acetic ester (10mL) to salt of wormwood (1.22mmol) and N-ethanoyl-3-amino methyl-benzsulfamide (1.22mmol) in 0 ℃, and stirs this mixture overnight under room temperature.This mixture is acidified to pH 2-3 with 5%HCl and extracts with EtOAc.Isolate organic layer, water and salt water washing, dry (MgSO 4), filter and concentrate in a vacuum.With silica gel column chromatography purifying residue, use the EtOAc wash-out, promptly 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-acetyl Base sulfamyl-benzyl acid amides, be solid product.MS：429(M+H)； 1H NMR(300MHz，CD 3OD)：δ3.95-4.00(d，3H)，4.85(s，3H)，7.22-7.34(m，H)，7.41-7.62(m，H)，7.66-7.83(d，2H)，7.88-7.95(d，H)，8.04(s，H)，8.12-8.23(m，H)，8.26-8.37(d，H)，9.26-9.34(m，2H)。
Embodiment 107
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-oxo-piperazine-1-alkylsulfonyl)-benzyl acid amides
Figure A20091013805301111
According to embodiment 106 similar methods, but replace N-ethanoyl-3-amino methyl-benzsulfamide with 4-(3-amino methyl-benzenesulfonyl)-piperazine-2-ketone, promptly make 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-oxo-piperazine-1-alkylsulfonyl)-benzyl acid amides, be solid product.MS：470(M+H)； 1HNMR(300MHz，DMSO-d 6)：δ3.16(s，4H)，3.57(s，2H)，4.63(d，2H)，7.34-7.47(m，H)，7.56-7.77(m，4H)，7.80(s，N-H)，8.01-8.18(m，2H)，8.28(d，H)，9.29(S，2H)，9.45(t，N-H)。
Embodiment 108
2-phenyl-pyrimidine-5-formic acid (2-sulfamyl-ethyl)-acid amides
Figure A20091013805301112
Add diisopropylethylamine (4.53mmol) to the DCM (15mL) of 2-phenyl-pyrimidine-5-formyl chloride (1.51mmol) and 2-amino-ethyl sulfonamide (1.51mmol) solution.Under room temperature, stir this mixture overnight.This mixture is concentrated in a vacuum.Water and DCM wash residual thing, promptly The 2-phenyl- Pyrimidine-5-formic acid (2-sulfamyl-ethyl)-acid amides, be solid product.MS：307(M+H)； 1HNMR(300MHz，DMSO-d 6)：δ3.25(q，2H)，3.67(m，2H)，6.93(s，N-H)，7.47-7.60(m，3H)，8.36-8.48(m，2H)，8.92-9.15(m，N-H)，9.16-9.36(m，2H)；IC 50＝55nM。
Embodiment 109
2-phenyl-pyrimidine-5-formic acid (2-dimethylamino alkylsulfonyl-ethyl)-acid amides
Figure A20091013805301121
According to embodiment 108 similar methods, but replace 2-amino-ethyl sulfonamide with 2-dimethylamino-ethyl sulfonamide, promptly make 2-phenyl-pyrimidine-5-formic acid (2-dimethylamino alkylsulfonyl-ethyl)-acid amides, be solid product.MS：334(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.76(s，6H)，3.29(t，2H)，3.62-3.73(m，2H)，7.45-7.60(m，3H)，8.42(m，2H)，9.06(bs，N-H)，9.20(s，2H)；IC 50＝82nM。
Embodiment 110
2-phenyl-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amides
Figure A20091013805301122
In 0 ℃ to 2-phenyl-pyrimidine-5-formic acid (400mg, 2mmol) suspension in DCM (10mL) successively add oxalyl chloride (0.2mL, 2.3mmol) and DMF (0.23mL, 3mmol).Stirred this mixture 20 minutes in 0 ℃, be warmed to room temperature and continue to stir 20min.Concentrate this mixture in a vacuum.Residue is dissolved in DCM and successively add 3-phenyl-[1,2,4] thiadiazoles-5-base amine (248mg, 1.4mmol) and NMP (0.5mL).Under room temperature, stirred this mixture 2 hours, and concentrate in a vacuum.In DCM, grind residue, promptly 2-phenyl-pyrimidine-5-formic acid (3-benzene Base-[1,2,4] thiadiazoles-5-yl)-acid amides(300mg), be solid product.MS：360(M+H)；IC 50＝30nM。
Embodiment 111
4-methyl-2-phenyl-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amides
Figure A20091013805301123
According to embodiment 110 similar methods, but replace 2-phenyl-pyrimidine-5-formic acid with 4-methyl-2-phenyl-pyrimidine-5-formic acid, promptly make
4-methyl-2-phenyl-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amidesMS：374(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.77(s，3H)，7.54-7.60(m，6H)，8.23(d，2H)，8.48(d，2H)，9.22(s，1H)，13.88(s，1H)。
Embodiment 112
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl) acid amides
Figure A20091013805301131
According to embodiment 110 similar methods, but replace 2-phenyl-pyrimidine-5-formic acid with 2-(3-fluoro-phenyl) pyrimidine-5-formic acid, promptly make 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles -5-yl) acid amidesMS：378(M+H)。
Embodiment 113
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides
Figure A20091013805301132
According to embodiment 110 similar methods, but replace 2-phenyl-pyrimidine-5-formic acid, and replace 3-phenyl-[1,2,4] thiadiazoles-5-base amine with tetrahydrochysene-pyrans-4-base amine with 2-(3-fluoro-phenyl) pyrimidine-5-formic acid, promptly make 2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amidesMS：302(M+H)； 1H NMR(300MHz，CD 3OD)：δ1.60-1.64(m，2H)，1.81-1.84(d，2H)，3.33(s，2H)，3.38-3.45(t，2H)，3.88-3.92(d，2H)，4.02-4.06(m，1H)，7.46(t，1H)7.62(q，1H)，8.14(d，1H)，8.29(d，1H)，8.70(d，1H)，9.27(s，2H)。
Embodiment 114
2-cyclohexyl-pyrimidine-5-formic acid phenyl amide
Figure A20091013805301141
Step 1. to the hexanaphthene amitraz hydrochloride (1g adds 3 in dry DMF 7.9mmol) (15mL) solution, 3-dimethoxy-2-methoxycarbonyl base third-1-alkene-sodium oxide (1.82g, 9.2mmol), with reaction mixture in 100 ℃ at N 2Heating is 3 hours in the atmosphere.Reaction is cooled to room temperature and adds entry (59mL).Extract this mixture with EtOAc.Organic layer is washed dry (MgSO with saturated brine 4), filter and concentrate in a vacuum, promptly 2-cyclohexyl-pyrimidine-5-methyl-formiate(0.5g, 29%) is solid product.MS：221(M+H)。
(0.97g, 4.39mmol) (1M, MeOH 4.39mL) (6mL) solution stirs under room temperature and spends the night step 2. with the LiOH aqueous solution with 2-cyclohexyl-pyrimidine-5-methyl-formiate.Evaporate MeOH in a vacuum, and handle this aqueous solution so that the pH value is adjusted between 2 and 3 with 3N HCl.Filter out the precipitation of generation, wash with water and dry in a vacuum, promptly 2-cyclohexyl-pyrimidine-5-formic acid(0.2g, 22%) is solid product.MS：207(M+H)。
Step 3. is with 2-cyclohexyl-pyrimidine-5-formic acid (100mg, 0.48mmol), I-hydroxybenzotriazole (74.2mg, 0.55mmol), with PS-DCC (505mg, 1.28mmol/g, 0.65mmol) the jolting 15 minutes under room temperature of the mixture of DMF (8mL) solution, and add aniline (30mg, 0.32mmol).This mixture of jolting is 18 hours under room temperature, and (388mg, 3.75mmol/g is 1.45mmol) also with this mixture jolting constantly at room temperature 18 hours to add the PS-triamine.Filter out solid and wash with DCM.Filtrate is concentrated in a vacuum, promptly 2-cyclohexyl-pyrimidine-5-formic acid phenyl Acid amides(45.6mg, 51%) is solid product.MS：282(M+H)；IC 50＝4960nM。
Embodiment 115
2-phenyl-pyrimidine-5-formic acid 3-amino-benzyl acid amides
Figure A20091013805301142
According to method similar to Example 8, but replace 2 with 3-amino-benzylamine, 2-dioxo 2,3-dihydro-1H-2 λ *6 *-benzo [c] isothiazole-5-base amine promptly makes 2-phenyl-pyrimidine-5-formic acid 3-amino-benzyl The base acid amides, be solid product.MS：305(M+H)； 1H NMR(300MHz，CD 3OD)：δ4.52(s，2H)，6.60-6.75(m，2H)，6.77(bs，N-H)，7.07(t，H)，7.47-7.59(m，3H)，8.44-8.53(m，2H)，9.23(s，2H)。
Embodiment 116
2-(3-pyridyl)-pyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides
Figure A20091013805301151
With 2-(3-pyridyl)-pyrimidine-5-formate hydrochlorate (237mg 1mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N, N-tetramethyl-urea hexafluorophosphate (380mg, 1mmol) mixture in dry DMF (15mL) is handled with diisopropylethylamine (0.36mL), and stirs 30min under room temperature.(355mg 1.5mmol) and under room temperature stirred this mixture 24 hours to add 3-methyl sulfamyl benzylamine hydrochloride.Remove desolvate and with residue at EtOAc and saturated NaHCO 3Distribute between the aqueous solution.Isolate organic phase, water and salt water washing, dry (MgSO 4), filter and concentrate in a vacuum.Grind residue with EtOAc.With the solid filtering that generates, with the ether washing, promptly 2-(3-pyridyl)-pyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides(185mg, 48%).MS：384(M+H)； 1H NMR(300MHz，DMSO-d 6)：δ2.43(d，3H)，4.65(d，2H)，7.45-7.55(q，1H)，7.60-7.75(m，3H)，7.80(s，1H)，8.72-8.80(m，2H)，9.35(s，2H)，9.55(m，2H)。
Embodiment 117
2-pyrazol-1-yl-pyrimidine-5-formic acid 4-sulfamyl-benzyl acid amides
Figure A20091013805301161
According to embodiment 116 similar methods, but replace 2-(3-pyridyl) pyrimidine-5-formate hydrochlorate, and replace 3-methyl sulfamyl benzylamine hydrochloride with 4-amino methyl-benzsulfamide hydrochloride with 2-pyrazol-1-yl-pyrimidine-5-formic acid, promptly make 2-pyrazol-1-yl-pyrimidine-5-formic acid 4-sulfamyl-benzyl acyl Amine, be solid product.MS：359(M+H)；IC 50＝266nM。
Embodiment 118
2-(2-methyl-thiazole-4-yl)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides
Figure A20091013805301162
According to embodiment 116 similar methods, but replace 2-(3-pyridyl) pyrimidine-5-formate hydrochlorate, and replace 3-methyl sulfamyl benzylamine hydrochloride, promptly make with tetrahydrochysene-pyrans-4-base amine with 2-(2-methyl-thiazole-4-yl)-pyrimidine-5-formic acid 2-(2-methyl-thiazole-4-yl)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4- Base)-acid amides, be solid product.MS：305(M+H)；IC 50＝82nM。
According to the general method described in the foregoing description, can make following compound:
2-phenyl-pyrimidine-5-formic acid (thiophene-2-ylmethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (4-methyl-oxazoles-2-yl)-acid amides,
Methoxyimino-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-ethyl acetate,
2-phenyl-pyrimidine-5-formic acid (5-methyl sulfane base-[1,3,4] thiadiazoles-2-yl)-acid amides,
2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-benzothiazole-5-ethyl formate,
(R)-2-phenyl-pyrimidine-5-formic acid (1-phenyl-ethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid [3-(1H-tetrazolium-5-yl)-phenyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid (1-amidino-piperidin-4-yl methyl)-acid amides,
5-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1H-indole-3-carboxylic acid acid amides,
2-phenyl-pyrimidine-5-formic acid [3-(2-amino-thiazolyl--4-yl)-phenyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid 4-[2-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-ethyl]-thiazol-2-yl }-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid [2-(tetramethyleneimine-1-alkylsulfonyl)-ethyl]-acid amides,
[3-({ [2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino }-methyl)-benzyl]-t-butyl carbamate,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(pyridine-2-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-hydroxyl-2,2-dimethyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxy-2-methyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(tetrahydrochysene-pyrans-4-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(4-hydroxyl-butyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(2-hydroxyl-oxyethyl group)-ethyl sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(tetrahydrochysene-furans-2-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-isobutyl-sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (5-sec.-propyl sulfamyl-pyridin-3-yl methyl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (5-methyl sulfamyl-pyridin-3-yl methyl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (2-methyl sulfamyl-pyridin-4-yl methyl)-acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid (2-methyl sulfamyl-pyridin-4-yl methyl)-acid amides and
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid (5-sec.-propyl sulfamyl-pyridin-3-yl methyl)-acid amides.
Differentiate the external test scheme of hematopoiesis PGD2 synthase inhibitor
Can be according to the enzyme inhibition activity of following arbitrary assay method test The compounds of this invention to the PGD2 synthase.
Assay method 1: fluorescence polarization determination method
As described in the example II of the open WO 2004/016223 of PCT.
Assay method 2: enzyme immunoassay (EIA) method
I. measure solution
A.0.1M K 2HPO 4/ KH 2PO 4The preparation of damping fluid (pH 7.4)
From 1M KH 2PO 4(Sigma, catalog number (Cat.No.) P-8709) preparation 0.1M KH 2PO 4
From Powdered K 2HPO 4(Fisher, BP363-500) preparation 0.1M K 2HPO 4
With 0.1M K 2HPO 4With 0.1M KH 2PO 4Mix, the pH value is adjusted to 7.4.
B.0.5% the preparation of gamma globulin
(Sigma, catalog number (Cat.No.) G-5009) joins 20mL 0.1MK with the 0.1g gamma globulin 2HPO 4/ KH 2PO 4Damping fluid (pH 7.4), preparation 1-ml/ bottle aliquots containig also is stored in-80 ℃.
C.100mM the preparation of GSH
307mg GSH (Sigma, catalog number (Cat.No.) G-6529) is joined 10mL 0.1MK 2HPO 4/ KH 2PO 4Damping fluid (pH 7.4), and be stored in-80 ℃.
D. the preparation of reaction buffer:
198mL 0.1M K 2HPO 4/ KH 2PO 4Damping fluid (pH 7.4)
2mM GSH-makes from 100mM GSH
0.4g glycerine
2mL 0.5% gamma globulin
0.4g glycerine and 2mL 0.5% gamma globulin are joined 198mL 0.1M K 2HPO 4/ KH 2PO 4Damping fluid (pH7.4).
Before mensuration, 0.4mL 100mM GSH joined 19.6ml reaction buffer (being enough to use) for two 96 orifice plates.
E.FeCl 2The preparation of/citric acid stop buffer: (8mg/mL FeCl 2, the 0.1M citric acid) and with the fresh FeCl of 40mg 2(IGN, catalog number (Cat.No.) 158046) joins in the 5ml 0.1M citric acid (Sigma, catalog number (Cat.No.) C0759).
The preparation of f.MOX reagent:
10%EtOH-joins the ultrapure H of 9mL with 1mL EtOH 2Among the O.
0.1g methoxyl group amine (Cayman, catalog number (Cat.No.) 400036/) is dissolved among the 10%EtOH (10mL).
Join in the MOX solution 0.82g sodium acetate (Cayman, catalog number (Cat.No.) 400037) and dissolving.
II. material and method
Dimethyl sulfoxide (DMSO) (DMSO; Sigma; Catalog number (Cat.No.) D2650)
The quick EIA test kit of PGD2-MOX (Caymen Chemical, catalog number (Cat.No.) 500151)
Before mensuration, in polypropylene tube internal cooling 10mL acetone, and 96 orifice plates of turning on ice.Except that the dilution of compound, institute all carries out on ice in steps.
III. diluted chemical compound
1. diluted compounds in DMSO
The volume of DMSO storing solution (μ L) DMSO(μL) Compound concentration (mM)
10mM storing solution 4 μ L 6μL 4
4mM storing solution 3 μ L 6μL 1.3333
1.33mM storing solution 3 μ L 6μL 0.4444
0.44mM storing solution 3 μ L 6μL 0.1481
0.148mM storing solution 3 μ L 6μL 0.0494
0.049mM storing solution 3 μ L 6μL 0.0165
0.016mM storing solution 3 μ L 6μL 0.0055
2. in the 96-orifice plate, each 2 μ L of the compound of above-mentioned every kind of concentration are diluted respectively and be 38 μ L reaction buffers and mix.
IV. the preparation of enzyme and substrate solution
1.0.39ng/ the preparation of μ L enzyme solution (being 0.35ng/ μ L finally behind the adding compound).
The people h-PGDS of 4 μ L (concentration is 4mg/mL) is mixed (making that enzyme concn is 40 μ g/mL) with 396 μ L reaction buffers.46.8 μ L (concentration is 40 μ g/mL) h-PGDS is added in the 4.753mL reaction buffer, make that cumulative volume is 4.8mL.
2. the preparation of substrate solution (PGH2): 0.375mL (concentration is 0.1mg/mL) PGH2 is joined in the 1.625mL acetone.
V. enzyme reaction:
1. the compound hole and the positive control hole (not containing compound) that 60 μ L enzyme solution are added polypropylene culture plate at the bottom of the U-shaped place on ice.
2. the 5%DMSO solution that 60 μ L reaction buffers and 6.6 μ L is dissolved in reaction buffer adds the negative control hole of culture plate.
3. 6.6 μ L being dissolved in after the dilution of reaction buffer compound adds the compound hole and mixes.
4. the 5%DMSO solution that 6.6 μ L is dissolved in reaction buffer joins the positive control hole.
5. hatch this culture plate 30min at least on ice.
6. the compound hole, negative control thing hole and the positive control hole that 20 μ L substrate (PGH2) solution are added 96 well culture plates at the bottom of the U-shaped on ice.
7. at the about 25-28min of this culture plate of cold house's inner drying.
8. drawing the above-mentioned enzyme solution of 45 μ L adds and fills 96 orifice plates of dry PGH2 and mix 3 times.Cultivate 1min on ice.
9. with 45 μ L FeCl 2Solution joins each hole and mixes.
10. add 90 μ L MOX solution and mixing.
11. hatch 30min at least in 60 ℃.
12. with EIA damping fluid dilute sample 2500X.
The VI.EIA assay method
Measure according to the described method of EIA test kit that Cayman provides.With the PGD2 aggregate level (pg/mL) in EIA test kit (Caymen Chemical, the catalog number (Cat.No.) 500151) working sample.
It is as follows to calculate the PGD2 amount:
Calculate positive control % according to following formula:
Positive control %=(compound value-negative control value)/(positive value-negative control value) x100.
Figure A20091013805301201
During the EIA of the sample of compound value=contain compound measures available from the PGD2 level (pg/mL) of typical curve
During the EIA of the sample of negative control value=do not contain enzyme measures available from the PGD2 level (pg/mL) of typical curve
During positive control value=contain enzyme but the EIA that do not contain the sample of compound measure available from the PGD2 level (pg/mL) of typical curve
Determine IC by the Excel fitting process 50, so that utilize this IC 504 parameter logarithmic models of curve and obtain x value when y=1/2Ymax.
The result
Compound in the scope of the invention has extremely produced 50% inhibition in the about 30 micromolar concentration ranges in about 1 nmole in fluorescence polarization determination method or EIA assay method.By the embodiment 8,9,33,34,82,83,84 of fluorescence polarization determination method acquisition and 114 IC 50, and by the embodiment 1,30,38,40,45,48,49,51,54,55,56,63,65,68,71,85,93,97,108,109,110,117 of EIA assay method acquisition and 118 IC 50Report in this paper " embodiment " joint.
The present invention can also other particular form be implemented and is not deviated from its spirit or essential characteristic.

Claims (29)

1. the compound of formula (I):
Wherein:
R 1Be aryl, heteroaryl or (C 5-C 6)-cycloalkyl, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy;
R 2Be hydrogen or (C 1-C 4)-alkyl;
R 3Be-P (=O)-(alkoxyl group) 2, or Y 1Y 2N-SO 2-,
Cycloalkyl, cycloalkenyl group, aryl, heteroaryl, heterocyclic radical, heterocycloalkenyl, or polynaphthene aryl, each group is optional to be replaced by following groups:
Acyl group, cyano group, nitro, halogen, hydroxyl, carboxyl, amidino groups,
R 5O-C(＝O)-C(＝N-OR 4)-、Y 1Y 2N-、Y 1Y 2N-C(＝O)-、Y 1Y 2N-C(＝O)-O-、Y 1Y 2N-SO 2-、
R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, Y 1Y 2N-(C 1-C 4)-alkylidene group-SO 2-(C 1-C 4)-alkylidene group-, or
Alkyl, alkenyl, alkynyl, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphinyl, or alkyl sulphonyl, each group is optional to be replaced by following groups:
Halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, amino, alkylamino, dialkyl amido, carboxyl, or alkoxy carbonyl, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by following groups: oxo base or alkyl, or
Aryl, heteroaryl, aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryloxy; or heterocyclic radical, each group is optional to be replaced by following groups: alkyl, haloalkyl, halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, or Y 1Y 2N-SO 2-, and
Work as R 3When being cycloalkyl, cycloalkenyl group, heterocyclic radical, heterocycloalkenyl or polynaphthene aryl, it is optional to be replaced by the oxo base;
L 1Be a key, or the optional (C that is replaced by hydroxyl 1-C 6)-alkylidene group, or work as R 3When being optional substituted cycloalkyl, cycloalkenyl group, aryl, heteroaryl, heterocyclic radical, heterocycloalkenyl or polynaphthene aryl, should (C 1-C 6)-alkylidene group also can choose wantonly by-P (=O)-(alkoxyl group) 2Replace;
R 4, R 5And R 6Be hydrogen or alkyl independently of one another,
R 7Be the optional alkyl that is replaced by hydroxyl, halogen or alkoxyl group, or
Aryl, heteroaryl, arylalkyl or heteroarylalkyl, the aryl of aryl wherein, heteroaryl or arylalkyl or heteroarylalkyl or heteroaryl can be chosen wantonly by following groups and replace: alkyl, haloalkyl, hydroxyl, carboxyl, alkoxy carbonyl, amino, alkylamino, dialkyl amido, halogen, alkoxyl group or halogenated alkoxy; And
Y 1And Y 2Be independently of one another:
Hydrogen,
The optional alkyl that is replaced by following groups:
Hydroxyl, carboxyl, halogen, amino, alkylamino, dialkyl amido, cycloalkyl amino, aminocarboxyl, alkyl amino-carbonyl, dialkyl amino carbonyl, cycloalkyl amino carbonyl,
The optional alkoxyl group that is replaced by hydroxyl,
Cycloalkyl, heterocyclic radical, aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen or haloalkyl, or
Optional by the cycloalkyl of carboxyl substituted, or
Y 1And Y 2With the nitrogen-atoms that links to each other with them, formation can be chosen wantonly to contain and be selected from other heteroatomic heterocyclic radical in oxygen, nitrogen or the sulphur, and wherein this heterocyclic radical is optional is replaced by alkyl or oxo base;
Condition is to work as L 1When being key, R 3Not the optional phenyl that replaces, the optional naphthyl that replaces, the optional benzimidazolyl-that replaces, the optional benzothiazolyl that replaces or the optional tetrazyl that replaces;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
2. according to the compound of claim 1, R wherein 1Be phenyl, five yuan or six membered heteroaryl, or (C 5-C 6)-cycloalkyl, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
3. according to the compound of claim 1, R wherein 1Be phenyl or five yuan or six membered heteroaryl, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
4. according to the compound of claim 1, R wherein 1Be phenyl or five yuan or six membered heteroaryl, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy, or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt, condition is to work as R 1When being phenyl or six membered heteroaryl, it only at the ortho position or a position be optionally substituted.
5. according to the compound of claim 1, R wherein 1Be phenyl, pyridyl, thiazolyl, or imidazolyl, oxo di azoly, each group is optional to be replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
6. according to the compound of claim 1, R wherein 1Be phenyl or pyridyl, each group can be in the ortho position or a position is optional is replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
7. according to the compound of claim 1, R wherein 1Be the optional phenyl that is replaced by following groups: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
8. according to the compound of claim 1, R wherein 1Be can be in the ortho position or the optional phenyl that is replaced by following groups in a position: halogen, (C 1-C 6)-alkyl, hydroxyl, (C 1-C 6)-alkoxyl group, (C 1-C 4)-haloalkyl or (C 1-C 4)-halogenated alkoxy; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
9. according to the compound of claim 1, R wherein 1It is the optional phenyl that is replaced by halogen; Or its hydrate, solvate or N-oxide compound; Or its pharmacologically acceptable salt.
10. according to the compound of claim 1, R wherein 1Be can be in the ortho position or the optional phenyl that is replaced by halogen in a position; Or its hydrate, solvate or N-oxide compound; Or its pharmacologically acceptable salt.
11. according to the compound of claim 1, wherein R 1Be 2-fluorophenyl or 3-fluorophenyl; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
12. according to the compound of claim 1, wherein R 2Be hydrogen; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
13. according to the compound of claim 1, wherein R 2It is methyl; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
14. according to the compound of claim 1, wherein L 1It is a key; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
15. according to the compound of claim 1, wherein L 1Be (C 1-C 3)-alkylidene group; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
16. according to the compound of claim 1, wherein L 1Be-CH 2-; Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
17. according to the compound of claim 1, wherein
R 3Be cycloalkyl, cycloalkenyl group, aryl, heteroaryl, heterocyclic radical, heterocycloalkenyl, or the polynaphthene aryl, each group all can be chosen wantonly by following groups and replace:
Acyl group, cyano group, nitro, halogen, hydroxyl, carboxyl, amidino groups,
R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-C (=O)-O-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, Y 1Y 2N-(C 1-C 4)-alkylidene group-SO 2-(C 1-C 4)-alkylidene group-, or
Alkyl, alkenyl, alkynyl, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphinyl, or alkyl sulphonyl, each group is optional to be replaced by following groups:
Halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, amino, alkylamino, dialkyl amido, carboxyl, or alkoxy carbonyl, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by following groups: oxo base or alkyl, or
Aryl, heteroaryl, aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryl oxygen base; or heterocyclic radical, each group is optional to be replaced by following groups: alkyl, haloalkyl, halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, or Y 1Y 2N-SO 2-, and
Work as R 3When being cycloalkyl, cycloalkenyl group, heterocyclic radical, heterocycloalkenyl or polynaphthene aryl, it is also optional to be replaced by the oxo base;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
18. according to the compound of claim 1, wherein R 3Be phenyl, pyridyl, thiazolyl, imidazolyl, oxo di azoly, imidazolyl, pyrimidyl, thiophenyl, oxazolyl, cycloalkyl, benzoxazolyl, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, THP trtrahydropyranyl, piperidyl, furyl, benzo [1,3] dioxolyl, benzothiazolyl, imidazolidyl, indazolyl, benzimidazolyl-, indyl, benzofuryl, or 1,3-dihydro-benzo [c] isothiazolyl, each group is optional to be replaced by following groups:
Acyl group, cyano group, nitro, halogen, hydroxyl, carboxyl, amidino groups,
R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-C (=O)-O-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, Y 1Y 2N-(C 1-C 4)-alkylidene group-SO 2-(C 1-C 4)-alkylidene group-, or
Alkyl, alkenyl, alkynyl, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphinyl, or alkyl sulphonyl, each group is optional to be replaced by following groups:
Halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-,
Aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, amino, alkylamino, dialkyl amido, carboxyl, or alkoxy carbonyl, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by following groups: oxo base or alkyl, or
Aryl, heteroaryl, aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryl oxygen base; or heterocyclic radical, each group is optional to be replaced by following groups: alkyl, haloalkyl, halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, or Y 1Y 2N-SO 2-, and
Work as R 3Be cycloalkyl, THP trtrahydropyranyl, piperidyl, imidazolidyl, or 1, during 3-dihydro-benzo [c] isothiazolyl, it is also chosen wantonly and is replaced by the oxo base;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
19. according to the compound of claim 1, wherein:
R 3Be phenyl, pyridyl, thiazolyl, imidazolyl, oxo di azoly, imidazolyl, pyrimidyl, thiophenyl, oxazolyl, cycloalkyl, benzoxazolyl, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, THP trtrahydropyranyl, piperidyl, furyl, benzo [1,3] dioxolyl, benzothiazolyl, imidazolidyl, indazolyl, benzimidazolyl-, indyl, benzofuryl, or 1,3-dihydro-benzo [c] isothiazolyl, each group is optional to be replaced by following groups:
Nitro, halogen, hydroxyl, carboxyl, amidino groups, R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphonyl, aryl, heteroaryl, or alkyl, it is optional to be replaced by following groups:
Halogen, carboxyl, alkoxy carbonyl, aryl or heteroaryl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by the oxo base, or
Heterocyclic radical, it is optional by Y 1Y 2N-replaces, and
Work as R 3Be cycloalkyl, THP trtrahydropyranyl, piperidyl, imidazolidyl, or 1, during 3-dihydro-benzo [c] isothiazolyl, it is also chosen wantonly and is replaced by the oxo base; And
Y 1And Y 2Be hydrogen, cycloalkyl independently of one another, or the optional alkyl that is replaced by following groups: hydroxyl, alkoxyl group, amino, alkylamino, dialkyl amido, heteroaryl, or the optional heterocyclic radical that is replaced by alkyl;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
20. according to the compound of claim 1, wherein R 3Be the optional phenyl that is replaced by following groups: acyl group, cyano group, nitro, halogen, hydroxyl, carboxyl, amidino groups,
R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-C (=O)-O-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, Y 1Y 2N-(C 1-C 4)-alkylidene group-SO 2-(C 1-C 4)-alkylidene group-, or
Alkyl, alkenyl, alkynyl, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphinyl, or alkyl sulphonyl, each group is optional to be replaced by following groups:
Halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-,
Aryl or heteroaryl, each group is optional to be replaced by following groups: alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, amino, alkylamino, dialkyl amido, carboxyl, or alkoxy carbonyl, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by following groups: oxo base or alkyl, or
Aryl, heteroaryl, aroyl, 4-hetaroylpyrazol, aryloxy, heteroaryl oxygen base; or heterocyclic radical, each group is optional to be replaced by following groups: alkyl, haloalkyl, halogen, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, alkoxy carbonyl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, or Y 1Y 2N-SO 2-,
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
21. according to the compound of claim 1, wherein:
R 3Be the optional phenyl that is replaced by following groups:
Nitro, halogen, hydroxyl, carboxyl, amidino groups, R 5O-C (=O)-C (=N-OR 4)-, Y 1Y 2N-, Y 1Y 2N-C (=O)-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, R 7-C (=O)-NR 6-, alkoxyl group, alkoxy carbonyl, alkylthio, alkyl sulphonyl, aryl, heteroaryl, or
The optional alkyl that is replaced by following groups:
Halogen, carboxyl, alkoxy carbonyl, aryl or heteroaryl ,-P (=O)-(alkoxyl group) 2, Y 1Y 2N-, Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, or
Heterocyclic radical or aryl-heterocyclic base, each group is optional to be replaced by the oxo base, or
Optional by Y 1Y 2The heterocyclic radical that N-replaces, and
Y 1And Y 2Be hydrogen, cycloalkyl independently of one another, or the optional alkyl that is replaced by following groups: hydroxyl, alkoxyl group, amino, alkylamino, dialkyl amido, heteroaryl, or the optional heterocyclic radical that is replaced by alkyl,
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
22. according to the compound of claim 1, wherein R 3Be the optional phenyl that is replaced by following groups:
Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, alkyl sulphonyl, or
By Y 1Y 2N-SO 2-, R 7-SO 2-NR 6The alkyl of-replacement;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
23. according to the compound of claim 1, wherein:
R 3Be the optional phenyl that is replaced by following groups:
Y 1Y 2N-SO 2-, R 7-SO 2-NR 6-, alkyl sulphonyl, or
By Y 1Y 2N-SO 2-, R 7-SO 2-NR 6The alkyl of-replacement; And
Y 1And Y 2Be hydrogen, cycloalkyl independently of one another, or the optional alkyl that is replaced by following groups: hydroxyl, alkoxyl group, amino, alkylamino, dialkyl amido, heteroaryl, or the optional heterocyclic radical that is replaced by alkyl;
Or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
24. compound, they are:
2-phenyl-pyrimidine-5-formic acid benzyl acid amides,
2-pyridin-4-yl-pyrimidine-5-formic acid phenyl amide,
2-pyridin-3-yl-pyrimidine-5-formic acid phenyl amide,
2-pyridine-2-base-pyrimidine-5-formic acid phenyl amide,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide,
2-(4-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide,
2-(2-fluoro-phenyl)-pyrimidine-5-formic acid phenyl amide,
2-phenyl-pyrimidine-5-formic acid (2,2-dioxo-2,3-dihydro-1H-2 λ * 6*-benzo [c] isothiazole-5-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid [1-(1H-imidazoles-2-ylmethyl-piperidin-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (6-dimethylamino-pyridin-3-yl methyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(2-tetramethyleneimine-1-base-ethyl)-benzoxazoles-6-yl]-acid amides,
2-phenyl-pyrimidine-5-formic acid 4-sulfamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(4-sulfamyl-phenyl)-ethyl]-acid amides,
(R)-2-phenyl-pyrimidine-5-formic acid [4-(2-Yang Dai oxazolidine-4-ylmethyl)-phenyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid (6-acetylaminohydroxyphenylarsonic acid pyridin-3-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (3-formamyl-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (3-methylamino formyl radical-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (4-hydroxyl-cyclohexyl)-acid amides,
4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-ethyl formate,
2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-ethyl acetate,
4-methyl-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-5-formic acid,
2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-acetate,
2-phenyl-pyrimidine-5-formic acid 4-methyl sulfamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 4-dimethylamino alkylsulfonyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid (3,5-two fluoro-phenyl)-acid amides,
2-phenyl-pyrimidine-5-pyridine carboxylic acid-2-base acid amides,
2-phenyl-pyrimidine-5-formic acid thiazol-2-yl acid amides,
2-phenyl-pyrimidine-5-formic acid (3-sulfamyl-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (2-oxo-1,2-dihydro-pyrimidine-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (4-sulfamyl-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid pyrimidine-4-base acid amides,
2-phenyl-pyrimidine-5-formic acid (1-pyridin-3-yl methyl-piperidin-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(2-oxo-imidazolidine-1-yl)-ethyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(1H-imidazol-4 yl)-ethyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-ylmethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (3-trifluoromethyl-phenyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (2H-pyrazole-3-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (1-methyl-piperidin-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid pyrimidine-2-base acid amides,
2-(3,5-two fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
2-(2,5-two fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
2-(4-difluorophenyl)-4-methylpyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides,
2-(2-pyridyl)-pyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides,
2-(3-pyridyl)-4-methyl-pyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-ethyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-oxyethyl group-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-cyclopropyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-hydroxyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-methoxyl group-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-methoxyl group-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(4-methoxyl group-butyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-cyclohexyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxyl-1,1-dimethyl-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-morpholine-4-base-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-piperidines-1-base ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(1-methyl-tetramethyleneimine-2-yl)-ethyl sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(1-ethyl-tetramethyleneimine-2-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(1H-imidazol-4 yl)-ethyl sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[3-(2-methyl-piperidines-1-yl)-propyl group sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-tetramethyleneimine-1-base propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-dimethylamino-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-diethylamino-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-dimethylamino-2,2-dimethyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(5-dimethylamino-amyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-diisopropylaminoethyl-ethyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-(methanesulfonamido-methyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-[(propane-2-sulfuryl amino)-methyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-methyl sulfamyl methyl-benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-(sec.-propyl sulfamyl-methyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(methylsulfonyl amino-methyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(propane-2-sulfuryl amino)-methyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl methyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(sec.-propyl sulfamyl-methyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (2-methylsulfonyl amino-pyridine-4-ylmethyl)-acid amides,
2-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides,
2-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrimidine-5-formic acid 4-sulfamyl-benzamide,
2-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(morpholine-4-alkylsulfonyl)-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 3,4-dimethoxy-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid (2-benzo [1,3] dioxole-5-base ethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (1H-indazole-5-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid 4-[1,2,3] thiadiazoles-5-yl)-the benzyl acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
4-methyl-2-pyridine-2-base-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 4-morpholine-4-base benzyl acid amides,
6-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1H-benzimidazolyl-2 radicals-methyl-formiate,
6-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1H-benzimidazolyl-2 radicals-formic acid,
2-phenyl-pyrimidine-5-formic acid (cumarone-5-ylmethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid 4-methylsulfonyl amino-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 4-formamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 3-(2-hydroxyl-ethyl sulfamyl)-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 4-(morpholine-4-alkylsulfonyl)-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid [2-(2-amino-4-methyl-thiazole-5-yl)-ethyl]-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methyl sulfamyl-benzyl acid amides,
4-{[(2-phenyl-pyrimidine-5-carbonyl)-amino]-benzyl }-diethyl phosphonate,
4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-butyl)-diethyl phosphonate,
4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-ethyl)-diethyl phosphonate,
Phenyl-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-methyl)-diethyl phosphonate,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-methylsulfonyl)-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (1-methylsulfonyl-piperidines-3-ylmethyl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (1-dimethylamino alkylsulfonyl-piperidines-3-ylmethyl)-acid amides,
2-(phenyl)-pyrimidine-5-formic acid 3-methylsulfonyl amino-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-ethanoyl sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-oxo-piperazine-1-alkylsulfonyl)-benzyl acid amides,
2-phenyl-pyrimidine-5-formic acid (2-sulfamyl-ethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (2-dimethylamino alkylsulfonyl-ethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amides,
4-methyl-2-phenyl-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl)-acid amides
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (3-phenyl-[1,2,4] thiadiazoles-5-yl) acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides,
2-cyclohexyl-pyrimidine-5-formic acid phenyl amide,
2-phenyl-pyrimidine-5-formic acid 3-amino-benzyl acid amides,
2-(3-pyridyl)-pyrimidine-5-formic acid-3-methyl sulfamyl-benzyl acid amides,
2-pyrazol-1-yl-pyrimidine-5-formic acid 4-sulfamyl-benzyl acid amides,
2-(2-methyl-thiazole-4-yl)-pyrimidine-5-formic acid (tetrahydrochysene-pyrans-4-yl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (thiophene-2-ylmethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid (4-methyl-oxazoles-2-yl)-acid amides,
Methoxyimino-2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-thiazole-4-yl }-ethyl acetate,
2-phenyl-pyrimidine-5-formic acid (5-methyl sulfane base-[1,3,4] thiadiazoles-2-yl)-acid amides,
2-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-benzothiazole-5-ethyl formate,
(R)-2-phenyl-pyrimidine-5-formic acid (1-phenyl-ethyl)-acid amides,
2-phenyl-pyrimidine-5-formic acid [3-(1H-tetrazolium-5-yl)-phenyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid (1-first miaow base-piperidin-4-yl methyl)-acid amides,
5-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-1H-indole-3-carboxylic acid acid amides,
2-phenyl-pyrimidine-5-formic acid [3-(2-amino-thiazolyl--4-yl)-phenyl]-acid amides,
2-phenyl-pyrimidine-5-formic acid 4-[2-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-ethyl]-thiazol-2-yl }-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid [2-(tetramethyleneimine-1-alkylsulfonyl)-ethyl]-acid amides,
[3-({ [2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carbonyl]-amino }-methyl)-benzyl]-t-butyl carbamate,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(pyridine-2-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(3-hydroxyl-2,2-dimethyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(2-hydroxy-2-methyl-propyl group sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(tetrahydrochysene-pyrans-4-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-(4-hydroxyl-butyl sulfamyl)-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[2-(2-hydroxyl-oxyethyl group)-ethyl sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-[(tetrahydrofuran (THF)-2-ylmethyl)-sulfamyl]-the benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid 3-isobutyl-sulfamyl-benzyl acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (5-sec.-propyl sulfamyl-pyridin-3-yl methyl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (5-methyl sulfamyl-pyridin-3-yl methyl)-acid amides,
2-(3-fluoro-phenyl)-pyrimidine-5-formic acid (2-methyl sulfamyl-pyridin-4-yl methyl)-acid amides,
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid (2-methyl sulfamyl-pyridin-4-yl methyl)-acid amides,
Or
2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-formic acid (5-sec.-propyl sulfamyl-pyridin-3-yl methyl)-acid amides, or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
25. pharmaceutical composition, it comprises the compound according to claim 1 or 24, or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt, and pharmaceutically acceptable carrier.
26. the method for treatment supersensitivity or inflammatory disorder comprises the compound according to claim 1 or 24 to described patient's administering therapeutic significant quantity in its patient of needs, or its hydrate, solvate or N-oxide compound, or its pharmacologically acceptable salt.
27. according to the method for claim 26, wherein this supersensitivity or inflammatory disorder are allergic rhinitises.
28. according to the method for claim 26, wherein this supersensitivity or inflammatory disorder are asthma.
29. according to the method for claim 26, wherein this supersensitivity or inflammatory disorder are chronic obstructive pulmonary diseases.
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Address before: Delaware

Patentee before: Auin Thurber holding Co.

Effective date of registration: 20160817

Address after: Delaware

Patentee after: Auin Thurber holding Co.

Address before: New jersey, USA

Patentee before: AVENTIS PHARMACEUTICALS Inc.